PL203663B1 - Cycloalkene derivatives, methods for the preparation of cycloalkene derivatives, pharmaceutical compositions containing cycloalkene derivatives, the use of cycloalkene derivatives - Google Patents

Description

Description of the invention The present invention relates to cycloalkene derivatives, methods for the preparation of cycloalkene derivatives, pharmaceutical compositions containing cycloalkene derivatives, and the use of cycloalkene derivatives. New cycloalkene derivatives that have an inducible inhibitory effect on the production of nitric oxide (NO) by nitric oxide synthetase and / or inhibit the production of inflammatory cytokines such as TNF-α, IL-1, IL-6, etc. . are useful as a prophylactic and therapeutic agent for diseases including heart disease, autoimmune diseases, inflammatory diseases, diseases of the central nervous system, infectious diseases, sepsis, septic shock, etc. ,. It is known that nitric oxide (NO) exhibits various important in vivo activities in mammals, such as vasodilation in the vascular system [Pharmacol. Rev. vol. 43, p. 109-142 (1991)], tumor-destroying and bactericidal effects in the immune system [Curr. Opin. Immunol. , Vol.3, pp. 65-70 (1991)] and acts as a neurotransmitter in the nervous system [Neuron, Vol. 8, p. 3-11 (1992)]. NO is produced mainly from L-arginine by the NO synthetase (NOS) and, as is currently known, exists in the form of three inducible isomeric forms, namely neural NOS, source NOS and inducible NOS (iNOS) [Cell, vol. 70 . p. 705-707 (1992)], and the former two are also considered constitutional NOS (cNOS) because of their mode of occurrence which contrasts with the latter iNOS. cNOS is present in the cells of the lymph nodes of the vessels and in neurons, and is dependent on calcium calmodulin and activated by various types of receptor stimulation to produce a low amount of NO, thus considering its contribution to the physiological regulatory effects described above above. On the other hand, iNOS is induced in macrophages and neutrophils by various cytokines and bacterial lipopolysaccharides (LPS) to produce a large amount of NO continuously, so it is assumed that it has not only pharmacological effects described above, but also that the cell and tissue damaging effects at the production site [Immunol. Today, Volume 13, pp. 157-160 (1992)]. Cells known to express iNOS other than those described above can, e.g. being c hepatocytes, Kupffer cells, glial cells, glial vascular cells, vascular lance endocytes, myoendocardium, cardiac muscle cells, mesangial cells, chondrocytes, synovial cells, pancreatic ß cells, osteoclasts etc. [FASEB J. , Vol. 6, pp. 3051-3064 (1992), Arch. Surg. , vol. 128, pp. 396-401 (1993), J. Biol. Chem. , Volume 44, pp. 27580-27588 (1994), J. Cell. Bloch. , Volume 57. p. 399-408 (1995)], and NO produced in these cells and tissues is known to be involved in a variety of diseases and pathologies. Accordingly, a substance that inhibits the production of NO by iNOS-inducible cells is believed to be effective as a prophylactic and therapeutic agent against various diseases such as sclerosis, myocarditis, cardiomyopathy, and hypoplasia. blood vessels of the brain, Alzheimer's disease, multiple sclerosis, septic shock, chronic rheumatoid arthritis, osteoarthritis, gastric ulcer, duodenal ulcer, colitis, ace ulcer, diabetes, keratitis, osteoporosis, inflammation lung disease, atheritis, psoriasis, transplant rejection and pain. From this point of view, several iNOS inhibitory compounds have been reported so far, such as the L-arginine analog [Pharmacol. Rev. vol. 43, p. 109-142 (1991)], an aminoguanidine [Br. J. Pharmacol. , vol.110, pp. 963-968 (1993)] and S-ethylisothiourea [J. Biol. Chem. , vol. 43, 26669-26676 (1994)]. However, none of these compounds have satisfactory activity and have an undesirable inhibitory effect not only on iNOS but also on cNOS, which is physiologically active. On the other hand, cytokines such as TNF-α, IL-1 and IL-6 are secreted by various cells such as monocytes, macrophages, lymphocytes, neutrophils, fibroblasts and endometrial cells, and are widely involved. in inflammation-related mechanisms of biological defense and immunity [The Cytokine Handbook, ed. second, Academic Press Limited (1994), Advances Immunol. , vol.62, pp. 257-304 (1996)], so they are referred to as inflammatory cytokines. The target cells for these cytokines cover a wide range of the inflammatory system, the vascular system, the central nervous system, the hematopoietic and endocrine systems, and therefore their biological activities are considered to be diverse, including representative biological activities. TNF-α and IL-1, which are considered (1) pyrogenic activity, (2) activation and promotion of chemotaxis of inflammatory cells such as macrophages and neutrophils, (3) induction of inflammatory cytokines and protein acute phase including IL-1, IL-6, IL-8, TNF-α and CSF and (4) enhancement of the production of various chemical mediators such as NO, O 2 -, PAF, prostaglandins, leukotrienes and proteases as well as with biological activity of IL-6, which are considered to be (1) PL 203 663 B1 3 induction of acute phase protein, (2) sc activity increasing the number of sc thrombocytes, (3) differentiation and activation lymphocytes and NK cells and (4) sc activity increasing the number of osteoclasts. However, these cytokines, when produced in excess or at the wrong place or time, have undesirable biological effects and have been proven to be involved in various diseases such as protozoa, bacteria, fungi, viruses and cancers, allergic diseases, chronic rheumatoid arthritis, pus, transplant rejection, anemia, arteriosclerosis, autoimmune disease, diabetes, diseases of the central nervous system, inflammatory bowel diseases, heart failure, atheritis, martian sc in atrobes, nephritis, osteoporosis, psoriasis, septic shock, etc. From this point of view, it is reported that substances that have an inhibitory or antagonistic effect on the production of TNF-α, IL-1 and IL-6, etc. [Eur. J. Immunol. , vol.18, p. 951-956 (1991), Immunol. , vol.83, pp. 262-267 (1994). Proc. Natl. Acad. Sci. , vol. 93, p. 3967-3971 (1997). J. Immune. , vol. 147, p. 1530-1536 (1991). Immunol. Today, Vol 12, pp. 404-410 (1991)] can be used as therapeutic agents against the diseases listed above. While several therapeutic agents are known for the treatment of heart failure, autoimmune diseases, inflammatory diseases and septic shock, none of them has had excellent pharmaceutical properties such as efficacy and safety. It is therefore an object of the invention to provide a prophylactic and therapeutic agent against heart failure, autoimmune diseases, inflammatory diseases and septic shock which would have improved pharmaceutical properties as mentioned above. To accomplish this goal, a drug has been deployed to produce a prophylactic and therapeutic agent for the diseases listed above which has an inhibitory effect on the production of NO and / or inflammatory cytokines by iNOS inducible cells, and finally succeeded. by synthesizing new compounds. The subject of the invention are cycloalkene derivatives of formula I: in which R is OR 1, where R 1 is E C 1-6 -alkyl, R 0 is hydrogen, ring n A is cycloalkene substituted by one or two substituents selected from C 1-6 alkyl group, halogen atom and phenyl group, Ar is C 6-14 aryl group and optionally have two halogen atoms. is group e of formula or formula and n is 2, or a pharmaceutically acceptable salt thereof. Preferably, ring A is a cycloalkene substituted with a C 1-6 alkyl group, a halogen atom or a phenyl group and Ar is a phenyl group and optionally having two halogen atoms. The invention also relates to cycloalkene derivatives of formula II: wherein R is OR 1, wherein R 1 is C 1-6 alkyl, optionally substituted by a substituent selected from (1) hydroxy, (2) a carboxyl group, (3) a C 1-6 alkoxycarbonyl group and (4) a C 6-10 -aryl group, R 0 is hydrogen or a C 1-6 alkyl group, or R and R 0 together represent a bond, Ar is a C 6-14 aryl group and optionally have a 1 to 3 substituents selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 4-alkoxycarbonyl, nitro, cyano, halo-C 1-4 -alkyl, halo-C 1-4 -alkoxy, C 1-4 -alkanoyl, 5-membered aromatic heterocyclic group selected from group 1 , 2,3-triazolyl, 1,2,4-triazolyl and tetrazolyl groups, C 1-4 alkoxycarbonyl-C 1-4 alkylcarbamoyl and 2,3-bis-t-butoxycarbonyl-guanidinomethyl groups. represents the group e of the formula: or of the formula and n is an integer from 1 to 3, provided that when (i) R 1 is an ethyl group, R 0 is a methyl group and Ar is an e phenyl group or (ii) R and R 0 together represent a bond and Ar is an e phenyl group, e 2-methylphenyl group, e 4-bromophenyl group, e 4-methoxyphenyl group or e 2,6-dimethylphenyl group, is a group of the formula: is a group e of the formula: or a pharmaceutically acceptable salt thereof. Of these compounds, the cycloalkene derivatives of formula III are preferred: wherein R 0 is hydrogen or C 1-6 alkyl, R 1 is C 1-6 alkyl and optionally substituted and through a substituent selected from (1) a hydroxyl group, (2) a carboxyl group, (3) a C 1-6 alkoxycarbonyl group and (4) a C 6-10 aryl group, Ar is an e C 6-14 aryl group and optionally have ac 1 to 3 substituents selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, nitro, cyano, halo C 1- 4-alkyl, halo-C 1-4 -alkoxy, C 1-4 -alkanoyl, 5-membered aromatic heterocyclic group selected from 1,2,3-triazolyl, 1,2,4- triazolyl and tetrazolyl groups, C 1-4 alkoxycarbonyl-C 1-4 -alkyl carbamoyl and 2,3-di-t-butoxycarbonyluanidinomethyl groups. is a group of formula or of formula and n is an integer from 1 or 3, provided that when Ar is phenyl, R 1 is e-ethyl and R 0 is methyl, the group is : is a group of the formula: or a pharmaceutically acceptable salt thereof. Especially preferred is a compound of formula III in which R 1 is ethyl. Also preferred is a compound of formula III in which R 0 is hydrogen. Also preferred is a compound of formula III wherein Ar is phenyl and optionally bearing substituents as defined above. Equally preferred is a compound of formula III in which Ar is a phenyl group substituted with a halogen atom and / or a C 1-4 alkyl group. Especially preferred is a compound of formula III in which Ar is a group e of the formula: wherein R 4 and R 5 are the same or different and represent a halogen atom or a C 1-4 alkyl group, an 'stands for an integer from 0 to 2. It is especially preferred that the halogen atom in the above compound is a fluorine atom or a chlorine atom. Also preferred is a compound of formula III in which the group of formula: is a group of formula a and n has the same meaning as defined above. The compound of formula III in which n is 1 is also preferred. Also preferred is a compound of formula III in which Ar is e phenyl and optionally having substituents as defined above and n is 1. Another group of preferred compounds are the cycloalkene derivatives of formula IV: in which Ar is a C 6-14 aryl group and optionally having 1 to 3 substituents selected from halogen, C 1-4 -alkyl, C 1-4 -alkoxy, C 1-4 -alkoxycarbonyl, nitro, cyano, halo-C 1-4 -alkyl, halo-C 1-4 -alkoxy, C 1-4 -alkanoyl, 5-membered aromatic heterocyclic group selected from 1,2,3-triazolyl group, 1,2,4-triazolyl group and tetrazolyl group, C 1-4 -alkoxycarbonyl-C 1-4 - alkylcarbamoyl and 2,3-di-t-butoxycarbonyloguanidinomethyl, n is an integer a from 1 to 3, or a pharmaceutically acceptable salt thereof. It is preferred that in the compound of formula IV Ar is a phenyl group, optionally having the substituents given above and n is 2. Yet another group of preferred compounds are the cycloalkene derivatives of formula V: wherein R 0 is hydrogen or C 1-6 alkyl, R 1 is C 1-6 alkyl, optionally substituted with a substituent selected from (1) hydroxy, (2) carboxyl, (3) C 1-6 alkoxycarbonyl and (4) C 6-10 -aryl, Ar is C 6-14 - aryl groups optionally have 1 to 3 substituents selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, nitro, cyano, halogen-C 1-4-alkyl, halo-C 1-4 -alkoxy, C 1-4 -alkanoyl, 5-membered aromatic heterocyclic group selected from 1,2,3-triazolyl, 1,2, 4-triazolyl and tetrazolyl groups, C 1-4 alkoxycarbonyl-C 1-4 -alkyl carbamoyl and 2,3-di-t-butoxycarbonyluanidinomethyl groups, wherein the group of the formula: If Ar is phenyl, R 1 is ethyl and R 0 is methyl, the group of formula: is group e of formula: or pharmaceutically acceptable salts thereof. It is preferred that in the compound of formula V, R 1 is ethyl. It is also preferred that in the compound of formula V, R 0 is hydrogen. It is also preferred that in the compound of formula V, Ar is phenyl and optionally having a substituents as defined above. It is particularly preferred that, in the compound of formula V, Ar represents a phenyl group substituted with a halogen atom and / or a C 1-4 alkyl group. It is also preferred that in the compound of formula V, Ar represents the group e of the formula: wherein R 4 and R 5 are the same or different and represent a halogen atom or a C 1-4 alkyl group, and n 'is an integer from 0 to 2. It is particularly preferred that the halogen atom is a fluorine atom or a chlorine atom. Also preferred is a compound of formula V in which the group of formula: is a group of formula: It is also preferred that a compound of formula V in which R 0 is a hydrogen atom and Ar is a phenyl group and substituted by a halogen atom. Especially preferred is the compound of formula V which is ethyl d-6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate, or a pharmaceutically acceptable salt thereof. Also preferred is the compound that is ethyl 6- [N- (2,4-dichlorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate, or a pharmaceutically acceptable salt thereof. The compound which is ethyl 6- [N- (2-chloro-4-methylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate or a pharmaceutically acceptable salt thereof is also preferred. The compound which is ethyl d-6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate, or a pharmaceutically acceptable salt thereof is also preferred. As a C 1-6 alkyl group in the case of R 0 or an optionally substituted C 1-6 alkyl group and in the case of R 1 it is preferred to use linear or branched alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. , it is particularly preferred that the alkyl group is e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc. A C 6-14 -aryl group optionally having substituents "as defined by Ar are, e.g. phenyl, naphthyl, biphenyl, anthryl, indenyl etc. and aryl having from 6 to 10 carbon atoms is particularly preferred, e.g. phenyl and naphthyl. Phenyl and the like are especially preferred. The "substituent" for a C 6-14 -aryl group is e.g. a halogen atom (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom, etc. ), lower alkyl (C 1-4) (e.g. methyl, ethyl, propyl, butyl etc. ), lower alkoxy (C 1-4) (e.g. methoxy, ethoxy, propoxy, butoxy etc. ), lower alkoxycarbonyls (C 1-4) (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl etc. ), e nitro group, e cyano group, lower haloalkyl (C 1-4) (e.g. trifluoromethyl, trifluoroethyl etc. halogenated lower (C 1-4) alkoxy (e.g. trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,3,3,3-pentafluoropropoxy etc. ), lower alkanols (C 1-4) (e.g. formyl, acetyl, propionyl etc. ), 5-membered aromatic heterocyclic groups (e.g. 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, lower alkoxycarbonyls (C 1-4), lower alkylcarbamoyls (C 1-4)) (e.g. butoxycarbonylmethylcarbamoyl, ethoxycarbonylmethylcarbamoyl, etc. ), lower 1,3-diacylguanidinoalkyl (C 1-4)) etc. 2,3-bis-t-butoxycarbonyloguanidinomethyl etc. ). Preferably, lower alkyl (C 1-4) (e.g. methyl, ethyl, propyl, butyl etc. ). More preferably, fluorine, chlorine and methyl are used. These substituents are substituted at substitutable positions on the hydrocarbyl aromatic groups and the number of substituents is from 1 to 3, more preferably from 1 to 2. When there are 2 or more substituents, they have the same or different meanings. The Ar typically used is e.g. phenyl, halophenyl, lower (C 1-4) alkylphenyl, lower (C 1-4) alkoxyphenyl, lower (C 1-4) alkoxycarbonylphenyl, carboxylphenyl, nitrophenyl, cyanophenyl, lower (C 1-4) halogenalkylphenyl, lower (C 1-4) haloalkoxyphenyl, lower (C 1-4) alkanoylphenyl, phenyl substituted 5-membered aromatic phenyl substituted with heterocycle, lower (C 1-4) alkoxy carbonyl lower (C 1 -4) alkylcarbamoylphenyl, lower (C 1-4) 1-3-diacylguanidinoalkylphenyl, halogenated (C 1-4) alkoxy-substituted phenyl, halogen-lower (C 1-4) alkoxycarbonyl-substituted phenyl, halo -cyano-substituted phenyl, halo-5-lon aromatic heterocyclo-substituted phenyl, halo- and lower (C 1-4) alkoxycarbonyl-lower (C 1-4) alkyl-carbamoyl-substituted phenyl etc. As Ar, halogenphenyl, lower (C 1-4) alkylphenyl, halogen lower (C 1-4) alkoxycarbonyl-substituted-phenyl and the like are preferably used. The halogenophenyls used are e.g. 2,3-difluorophenyl, 2,3-dichlorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2,5-difluorophenyl, 2,5-dichlorophenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 3, 4-difluorophenyl, 3,4-dichlorophenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 2-fluorophenyl, 2-chlorophenyl, 3-fluorophenyl, 3-chlorophenyl, 4-fluorophenyl, 4-chlorophenyl, 2- fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, 4-bromo-2-fluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6-trifluorophenyl etc. As lower (C 1-4) alkylphenyls, 2-ethylphenyl, 2,6-diisopropylphenyl and the like are preferably used. and as lower (C 1-4) alkoxyphenyls, it is preferred to use e.g. 4-methoxyphenyl etc. As lower (C 1-4) alkoxylcarbonylphenyls, 2-ethoxycarbonylphenyl, 2-methoxycarbonylphenyl, 4-methoxycarbonylphenyl and the like are preferably used. and the lower halogen (C 1-4) alkylphenyl is preferably used e.g. 2-trifluoromethylphenyl etc. and as lower halogen (C 1-4) alkoxyphenyl, 2-trifluoromethoxyphenyl, 4- (2,2,3,3,3-pentafluoropropoxy) phenyl and the like are preferably used. As lower (C 1-4) alkanoylphenyl, e.g. preferably 2-acetylphenyl etc. is used. and as a 5-membered aromatic phenyl substituted with a heterocycle e.g. preferably 4- (2H-1,2,3-triazol-2-yl) phenyl, 4- (2H-tetrazol-2-yl) phenyl, 4- (1H-tetrazol-1-yl) phenyl, 4 - (1H-1,2,3-triazol-1-yl) phenyl etc. and as lower (C 1-4) alkoxy carbonyl lower (C 1-4) alkylcarbamoylphenyl e.g. 4- (N-ethoxycarbonylmethylcarbamoyl) phenyl etc. are preferably used. and the lower 1,3-diacylguanidino (C 1-4) alkylphenyl is preferably used e.g. 4- (1,3-bis-t-butoxycarbonyluanidinomethyl) phenyl etc. The phenyl substituted with halogen and lower (C 1-4) alkyl are preferably used e.g. 2-fluoro-4-methylphenyl, 2-chloro-4-methylphenyl, 4-fluoro-2-methylphenyl etc. and as phenyl substituted with halogen and lower (C 1-4) alkoxycarbonyl it is preferably used e.g. 2-chloro-4-methoxycarbonylphenyl etc. and as phenyl substituted with halogen and cyano, e.g. 2-chloro-4-cyanophenyl etc. and the halogen substituted phenyl and the 5-ion aromatic heterocycle are preferably e.g. 2-fluoro-4- (1H-1,2,4-triazol-1-yl) phenyl etc. and as phenyl substituted with halogen and lower (C 1-4) alkoxycarbonyl lower (C 1-4) alkylcarbamoyl, e.g. 2-chloro-4- (N-t-butoxycarbonylmethylcarbamoyl) phenyl, 2-chloro-4- (N-ethoxycarbonylmethylcarbamoyl) phenyl etc. More specifically, Ar is preferably phenyl, a phenyl substituted with 1 to 3 (especially 1 to 2) halogen atoms (e.g. 2,3-difluorophenyl, 2,3-dichlorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2,5-difluorophenyl, 2,5-dichlorophenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 3, 4-difluorophenyl, 3,4-dichlorophenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 4-bromo-2-fluorophenyl, 2-fluorophenyl, 2-chlorophenyl, 3-fluorophenyl, 3-chlorophenyl, 4-fluorophenyl, 4-chlorophenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl etc. ), phenyl substituted with halogen and lower (C 1-4) alkyl (e.g. 2-chloro-4-methylphenyl, 4-fluoro-2-methylphenyl etc. ) etc. Of these, phenyl substituted with 1 to 3 (especially 1 to 2) halogen atoms (e.g. 2,3-dichlorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 2-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 2-chloro-4-fluorophenyl, 2,4,5- trifluorophenyl, etc. ), phenyl substituted with halogen and lower (C 1-4) alkyl (e.g. 2-chloro-4-methylphenyl, 4-fluoro-2-methylphenyl etc. ) etc. Particularly preferred are the? 2,4-difluorophenyl, 2-chlorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-4-methylphenyl and the like. and 2,4-difluorophenyl, 2-chloro-4-fluorophenyl. When ring n A is substituted with 2 substituents, these may be the same or different. A single carbon atom may be substituted with 2 substituents. As substituents for the ring A, preferably 1 or 2 C 1-6 alkyl (e.g. (C 1-4) alkyl such as methyl, tert-butyl and the like ), phenyl, halogen (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom, etc. ) etc. A group of formula: is preferably a group of formula: A group of formula is preferably a group of formula: If n is an integer from 1 to 3, preferably n is 2. When the compounds represented by Formulas I, II, III, IV and V have stereoisomers and optical isomers, each of these optical stereisomers and isomers and mixtures thereof are within the scope of the invention. A prodrug for a compound of the invention, i.e. a compound of formula (I) or (II), is a compound that converts to a compound of formula (I) or (I) under physiological conditions upon reaction with an enzyme or a hydrochloric acid, so that the compound is enzymatically oxidized, reduced, or hydrolysed to form a compound of formula (I) or (II), and the compound is hydrolyzed by a hydrochloric acid to form a compound of formula (I); or (II). A prodrug for a compound of formula (I) or (II) can be e.g. obtained by subjecting an amino group of a compound of formula (I) or (II) to acylation, alkylation or phosphorylation (e.g. a compound obtained by subjecting an amino group in a compound of formula (I) or (II) eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation and tert-butylation); a compound obtained by subjecting the hydroxy group of a compound of formula (I) or (II) to acylation, alkylation, phosphorylation and borination (e.g. a compound obtained by subjecting the hydroxy group in a compound of formula (I) or (II) to acetylation, palmitoylation, propanoylation, pivaloylation, succinylation, fumarylation, alanylation and dimethylaminomethylcarbonylation); a compound obtained by subjecting the carboxyl group of a compound of formula (I) or (II) to esterification or amidation (i.e. , a compound obtained by subjecting a carboxyl group of a compound of formula (I) or (II) to ethyl esterification, phenyletherification, carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyl xymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-oxomethyl) -dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification and methylamidation) etc. Each of these compounds can be prepared from a compound of formula (I) or (II) by a generally known method. A prodrug for a compound of formula (I) or (II) may also be a compound that converts to a compound of formula (I) or (II) under physiological conditions such as described in "lyakuhin no Kaihatsu (Developments of Pharmaceuticals) ", vol. 7, Design of Molecules, p. 163-198, Published by Hirokawa Shoten (1990). Alternatively, a compound according to the invention (e.g. converting a salt to a salt with an inorganic base, an organic base, an inorganic acid, an organic acid, an acidic or a basic amino acid. Inorganic salt with alkali can be e.g. an alkali metal salt such as sodium and potassium, an alkaline earth metal such as calcium and magnesium, aluminum and ammonium, and an organic base salt such as e.g. was a salt with a base such as trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine or N, N'-dibenzylethylenediamine. A salt with an inorganic acid can e.g. A salt with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid or phosphoric acid, and a salt with an organic acid can be e.g. a salt with an acid such as formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid. A salt with a basic amino acid can be e.g. a salt with an amino acid such as arginine, lysine, or ornithine, and a salt with an acidic amino acid can be e.g. salt with aspartic acid or glutamic acid. The compounds of the invention may be hydrates or in anhydrous form, and likewise prodrugs for the compounds of the invention of formula (I) or (II). Moreover, the compound of the invention may be labeled with radioisotopes (e.g. 3H, 14C, 35S, 125I etc. ), and the prodrug for the compound of the invention (I) or (II) may also be similarly labeled. When an asymmetric carbon atom is present in a cycloalkene ring in a compound according to the invention, it is possible, for example, to as described above, present as any of the two stereoisomers (optical isomers) which can be prepared separately if necessary. PL 203 663 B1 11 For example a single isomer of the formula: in which each symbol has the meaning as defined above, or of the formula: in which each symbol has the meaning as defined above, or the formula: in which each symbol has the meaning as defined above, in which the group of the formula : in which n is as defined above in the starting compound, represents the group e of the formula: in which n is as defined above and * represents a single spatial configuration of the indicated carbon atom or a single isomer of a compound of formula (III), i.e. , a compound of the formula: in which each symbol is as defined above, it may be used to perform a reaction as described above to give a single isomer of a compound according to the invention. When the compound of the invention is a mixture of two or more isomers, conventional separation methods may be used to separate the individual isomers, such as a method in which a salt is formed with an optically active acid (e.g. camphorsulfonic acid, etc. ) or an optically active base (e.g. 1-methylbenzylamine etc. ), and then it is separated by various chromatographic methods (e.g. liquid chromatography in optically active columns) and can be used by fractional recrystallization. The subject of the invention is also a process for the preparation of a compound represented by the formula III, characterized in that the compound of the formula: in which R 1 and n have the same meanings as given above and X 1 is a halogen atom, or a pharmaceutically acceptable salt thereof, is reacted with a compound of the formula: wherein R 0 and Ar have the same meaning as given above or with a pharmaceutically acceptable salt thereof. The subject of the invention is also a process for the preparation of a compound represented by formula IV, characterized in that a compound of formula: wherein n and Ar is as defined above, or a pharmaceutically acceptable salt thereof, is subjected to a closure reaction the ring in the presence of a condensing agent which is N, N'-dicyclohexycarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, diethyl cyanophosphate, diphenylphosphorylazide or carbonyldiimidazole. The invention also relates to a process for the preparation of a compound represented by the formula V, characterized by a compound of the formula: wherein R 1 is as defined above, and X 1 is a halogen atom or a paint thereof. a pharmaceutically acceptable salt, is reacted with a compound of the formula: wherein R 0 and Ar are as defined above, or a pharmaceutically acceptable salt thereof. If the leaving group and defined by X 1 is a halogen atom (e.g. chlorine atom, bromine atom, iodine atom, etc. ) etc. , it is preferably a chlorine atom. Methods for the preparation of a compound of the formula: where n is 1 or 2 and a compound of the formula: where n is 1 or 2 are found in the Journal of the American Chemical Society, Vol. 101, p. 6981-699 / (1979). Moreover, a method for the preparation of a compound of the formula; where Ar is phenyl, 2-methylphenyl, 4-bromophenyl, 4-methoxyphenyl, or 2,6-dimethylphenyl, see Tetrahedron, Vol 52, p. 783-790 (1996). The reaction according to the process of the invention can be carried out with or without a base, in a solvent which does not reverse the reaction, or without the use of a solvent. In this reaction, the amount of the compound or salt used in the reaction is preferably about 1 to about 5 times (molar ratio), more preferably about 1 to about 2 times (molar ratio) of the compound or its salt. As a rule, c, e.g. inorganic bases (e.g. sodium hydride, potassium hydride, sodium hydroxide, etc. ), organic bases (e.g. triethylamine, pyridine, diisopropylethylamine, etc. ), preferably organic bases such as triethylamine. The amount of base used is preferably about 0.5 to about 5 times (molar ratio), more preferably about 0.9 to about 2 times (molar ratio) of the compound of the solvent used in this reaction, which does not affect the reaction in a reversible manner, it may be, for example, sulfoxide (e.g. dimethyl sulfoxide, etc. ), ether (e.g. diethyl ether, tetrahydrofuran, dioxane, etc. ), nitrile (e.g. acetonitrile, etc. ), aromatic in hydrocarbon (e.g. benzene, toluene, xylene etc. ), halogenated into hydrocarbon (e.g. dichloromethane, chloroform, 1,2-dichloroethane etc. ), an ester (e.g. ethyl acetate), amide (e.g. dimethylformamide, acetamide, dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidone, etc. ) etc. Any of these solvents may be used alone or in a mixture in appropriate proportions. This reaction is preferably carried out at a temperature of about -10 ° C to 100 ° C, more preferably at about 0 ° C to 60 ° C. The reaction time is from about 0.5 to about 50 hours, preferably about 0.5 hours to about 30 hours. Compounds, which are products of this reaction, can be produced as a single compound or in a mixture. When R 0 in the resulting compounds represents a hydrogen atom, the ring-closing reaction can take place under the same reaction and / or isolation conditions as for the compound of formula Compound (III) according to the invention, can be produced by by reacting a compound of the formula: in which each symbol has the meaning defined above, or a salt thereof, with a compound of the formula: R 0 X 1 in which X 1 represents the group e leaving a (e.g. a chlorine atom (e.g. chlorine atom, bromine atom, iodine atom, etc. ) or the group e of the formula -O 3 SR 3, in which R 3 is a lower alkyl group having a 1 to 4 carbon atoms or an optionally substituted phenyl and R 0 is an optionally substituted hydrocarbyl aliphatic group a etc. or by hydrolyzing the product obtained in the above reaction by a known method. The reaction in question can be performed in the absence or presence of a base, in a solvent which does not affect the reaction reversibly, or in the absence of the use of a solvent. In this reaction, the compound R 0 X 1 is preferably used in an amount about 1 to 5 times (molar ratio), more preferably about 1 to about 2 times (molar ratio), relative to the Alkaline compound. which can be used for example inorganic bases (e.g. in potassium egate, sodium hydride, potassium hydride, sodium hydroxide etc. ), organic bases (e.g. triethylamine, pyridine, diisopropylethylamine, etc. ). The amount of base (if used) is preferably about 0.5 to about 5 times (molar ratio), more preferably about 0.9 to about 2 times (molar ratio) with respect to the compound. in the above reaction, which does not affect the reaction in a reversible manner, may be e.g. sulfoxide (e.g. dimethyl sulfoxide, etc. ), ether (e.g. diethyl ether, tetrahydrofuran, dioxane etc. ), nitrile (e.g. acetonitrile, etc. ), aromatic in hydrocarbon (e.g. benzene, toluene, xylene etc. ), halogenated into hydrocarbon (e.g. dichloromethane, chloroform, 1,2-dichloroethane etc. ), an ester (e.g. ethyl acetate), amide (e.g. dimethylformamide, acetamide, dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidone, etc. ) etc. Each of these solvents can be used alone or in a mixture of two or more solvents in appropriate proportions. The reaction is preferably carried out at a temperature of about -10 ° C to 100 ° C, more preferably at about 0 ° C to 60 ° C. The reaction time ranges from about 0.1 to about 50 hours, preferably from about 0.5 hours to about 10 hours. Compound (III) according to the invention can be produced by e.g. by reaction of a compound of the formula: in which M is a hydrogen atom or an alkali metal (e.g. lithium, sodium, potassium, etc. ), and each of the other symbols has the meaning as defined above, or a salt thereof, with a compound of the formula: R 1 -X 1 wherein each symbol is as defined above, or a salt thereof. The reaction of the above compounds may be carried out in the absence or presence of a base, in a solvent which does not reverse the reaction, or without the use of a solvent. In this reaction, the compound R 1 -X 1 is preferably used in an amount of about 1 to about 10 times (molar ratio), more preferably about 1 to about 5 times (molar ratio), the base compound which is you can use it, for example inorganic bases (e.g. sodium hydride, potassium hydride, sodium hydroxide etc. ), organic bases (e.g. triethylamine, pyridine, diisopropylethylamine etc. ). Preferably, the base is used in an amount of about 0.5 to about 5 times (molar ratio), more preferably about 0.9 to about 2 times (molar ratio) with respect to the compound. in a reaction that does not affect the reaction in a reversible manner, e.g. sulfoxide (e.g. dimethyl sulfoxide, etc. ), ether (e.g. diethyl ether, tetrahydrofuran, dioxane etc. ), nitrile (e.g. acetonitrile and the like), aromatic hydrocarbon (e.g. benzene, toluene, xylene etc. ), halogenated into hydrocarbon (e.g. dichloromethane, chloroform, 1,2-dichloroethane etc. ), an ester (e.g. ethyl acetate), amide (e.g. dimethylformamide, acetamide, dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidone, etc. ) etc. Each of these solvents can be used alone or in a mixture of two or more solvents in appropriate proportions. The reaction is preferably carried out at a temperature of about -10 ° C to 150 ° C, more preferably at about 0 ° C to 120 ° C. The reaction time is from about 0.5 to about 50 hours, preferably from about 0.5 hours to about 30 hours. The compound (III) according to the invention, in which R 1 is lower (C 1-4) alkyl, can be prepared by reaction of a compound of the formula: in which R 1b is a hydrogen atom of lower (C 1-6) ) alkyl and each of the other symbols is as defined above, or a salt thereof, with a compound of the formula: R 1c -OH wherein R 1c is lower (C 1-4) alkyl. The reaction can be carried out in the presence of an acid in a solvent which does not affect the reaction in a reversible manner, or without the use of a solvent. In this reaction, the R 1c-OH compound is used in excess of the second reagent typically by about 10 to about 300 times (molar ratio). As acid, it is possible to use e.g. inorganic acid (e.g. sulfuric acid, hydrochloric acid, phosphoric acid, etc. ) or organic (e.g. toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, etc. ) and is preferably used in an amount of about 0.001 to about 50 times (molar ratio), more preferably about 0.1 to about 5 times (molar ratio) with respect to the compound (Iz). The solvent used in the reaction, which does not interfere with the reaction in a reversible manner, may e.g. sulfoxide (e.g. dimethyl sulfoxide, etc. ), ether (e.g. diethyl ether, tetrahydrofuran, dioxane etc. ), nitrile (e.g. acetonitrile, etc. ), aromatic in hydrocarbon (e.g. benzene, toluene, xylene etc. ), halogenated in hydrocarbon (eg. dichloromethane, chloroform, 1,2-dichloroethane etc. ), amide (e.g. dimethylformamide, acetamide, dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidone, etc. ) etc. Each of these solvents can be used alone or in a mixture of two or more solvents in appropriate proportions. The reaction is preferably carried out at a temperature of about 0 ° C to 150 ° C, more preferably at about 10 ° C to 120 ° C. The reaction time is from about 1 to about 300 hours, preferably about 10 hours to about 200 hours. Compound (II) according to the invention, in which R and R 0 together form a bond and a group of formula: in which n is as defined above is a group e of formula: in which n is as defined above hey, you can know e.g. producing a ring-closing compound of the formula wherein each symbol has the meaning as defined above, or a salt thereof. Thus, the ring closure reaction can usually be carried out by the method used to dehydrogenate the carboxyl and amine groups to condense to an amide bond, such as described in "Izumiya et. al. , Basics and Experiments of Peptyde Synthesis, Maruzen (1985) ". More typically, the ring-closing reaction can be performed by contacting compound (IIb) with a condensing agent in a solvent that does not reverse the reaction, with or without a base, and in the presence or absence of a base. without additionals. As a solvent in this reaction which does not affect the reaction in a reversible manner, it is possible to use, e.g. sulfoxide (e.g. dimethyl sulfoxide, etc. ), ether (e.g. diethyl ether, tetrahydrofuran, dioxane etc. ), nitrile (e.g. acetonitrile, etc. ), into an aromatic hydrocarbon (e.g. benzene, toluene, xylene etc. ), halogenated in hydrocarbon (eg. dichloromethane, chloroform, 1,2-dichloroethane etc. ), an ester (e.g. ethyl acetate etc. ), amide (e.g. dimethylformamide, acetamide, dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidone, etc. ) etc. Each of these solvents can be used alone or in a mixture of two or more solvents in appropriate proportions. Yes, and the rules can be c, e.g. an organic base (e.g. triethylamine, pyridine, diisopropylamine, etc. ) etc. The base is preferably used in an amount of about 0.01 to about 100 times (molar ratio), more preferably about 0.1 to about 10 times (molar ratio), with respect to the compound (IIb). As an additive, c can be used as described above, e.g. active esterifying agent (e.g. 1-hydroxybenzotriazole, N-hydroxysuccinimide etc. ). Preferably, the amount of sc of the additive used is about 0.01 to about 100 times (molar ratio), more preferably about 0.1 to about 10 times (molar ratio) with respect to the compound (IIb). The condensing agent used is N, N'-dicyclohexycarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, diethyl cyanophosphate, diphenylphosphorylazide, and carbonyldiimidazole is particularly preferred, with N, N'N'hexycarbodiimidylcarbodiimidylcarbodiimide and diethyl cyanophosphate. Preferably, the sc amount of the thickening agent (when used) is about 0.01 to about 100 times (molar ratio), more preferably about 0.1 to about 10 times (molar ratio) of the compound (IIb ). The reaction temperature is preferably about -10 ° C to 100 ° C, more preferably about 0 ° C to 50 ° C. The reaction time is from about 0.5 to about 50 hours, preferably about 0.5 hours to about 30 hours. The compounds according to the invention obtained in this way can be isolated and purified by generally known methods such as extraction, condensation, neutralization, filtration, crystallization, recrystallization, chromatography, etc. When the compound according to the invention obtained in this way is a compound which is a mixture of two compounds and in each of them a group of the formula: in which n is as defined above, represents the group e of the formula: where n is as defined above, and represents a group e of the formula: in which n is as defined above, respectively, then the separation can be carried out by known isomer separation methods such as silica gel chromatography using ethyl acetate / water as eluent, column chromatography with octadecyl packing using methanol / water / acetic acid, etc. So when the product is a mixture of two compounds, and in each of them the group of formula: in which n is as defined above, means the group e of the formula: in which n is as defined above, and the group e of the formula in which n has the meaning defined above, respectively, then the separation can be carried out in a similar manner. The compound (Ile), in which R 1 is ethyl and X 1 is chlorine, may e.g. producing by a method according to the following scheme. The method for producing the starting compound (IIc) according to this scheme is generally known, and it can be e.g. as described in Tetrahedron, Vol. 28, pp. 5923 (1972) and vol. 30, pp. 3753 (1974) or with analogous methods. The method for the preparation of a compound in which R 1 is ethyl, X 1 is a chlorine atom and where n is 1, of the formula: and in which n is 2, of the formula: is generally known, and it can be e.g. . as described in the Journal of the American Chemical Society, Vol. 101, pp. 6981 (1979) or with similar methods. The method for the preparation of a compound in which R 1 is methyl is chlorine and n is 2, of the formula: is generally known, and can be e.g. as described in Bioorganic and Medicinal Chemistry Letters, Vol. 5, p. 325 (1995) or by analogous methods. For the production of other compounds falling within the definition of the starting compound, the above-described method or analogous methods can be used. The output compound (IIb) or (ly) can be known e.g. producing a method according to the following patterns. wherein each symbol has the meaning as defined above, and wherein each symbol has the meaning defined above. The method for the preparation of the compound (s), in which M is a hydrogen atom, R2 is methyl, Ar is phenyl, n is 2 and the group of formula: is a group of formula e, which is a compound of formula: is generally known, and may be as described in the Journal of the American Chemical Society. volume. 101, pp. 6981 (1979) or by analogous methods. The starting compound or intermediate obtained as described above can be isolated from a reaction mixture and purified by generally known methods such as extraction, concentration, neutralization, filtration, crystallization, recrystallization, column chromatography, chromatography. thin-layer, etc. It can also be used directly in the next step without isolation. When the resulting starting substance or intermediate is a mixture of two compounds, wherein the group of the formula: wherein n is as defined above, represents the group e of the formula: where n is as defined above and represents the group e of the formula: in which n is as defined above, respectively, then the separation can be performed by known isomer separation methods such as silica gel chromatography using ethyl acetate / water as eluent, octadecyl column chromatography with using the methanol / water / acetic acid phase as eluent etc. So, when the product is a mixture of two compounds, in each of which the group of formula: wherein n is as defined above, represents the group e of the formula: wherein n is as defined above and represents a group e of the formula: wherein n is as defined above, respectively, then the separation can be performed similarly. The invention also relates to a pharmaceutical composition containing the active ingredient and pharmaceutically acceptable excipients, the active ingredient containing the cycloalkene derivative of formula I or its pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition containing the active ingredient and pharmaceutically acceptable excipients, the active ingredient containing the cycloalkene derivative of formula II or its pharmaceutically acceptable salts. Of the latter, a composition which comprises a compound of formula III, IV or V or a pharmaceutically acceptable salt thereof is especially preferred. The compounds of the invention are administered safely to humans as such or in admixture with suitable pharmacologically acceptable carriers, excipients and diluents, in dosage forms such as an oral preparation (e.g. powder, granule, tablet, capsule etc. ), parenteral preparation (e.g. injection preparation, skin preparation (e.g. intranasal preparation, intradermal preparation, etc. ), suppositories (e.g. rectal and vaginal suppositories, etc. ) as well as with other oral or parenteral pharmaceutical compositions. Each of these preparations can be prepared by any generally known method which is usually used for the preparation of a pharmaceutical preparation. The amount of the compound of the invention which may be incorporated into the formulation may vary depending on the dosage form and is preferably about 10 to 95% by weight in the form of the oral formulation described above and about 0.001 to about 95% by weight for the parenteral formulation described above. For example an injectable formulation can be prepared by mixing a compound of the invention together with a solubilizing agent (e.g. ß-cyclodextrin, etc. ), dispersant (e.g. Tween 80 (Atlaspowder USA), HC060 (Nikko Chemicals), carboxymethyl cellulose, sodium alginate, etc. ), a preservative (eg. methylparaben, propylparaben, benzyl alcohol, chlorobutanol etc. ), an isotonic agent (eg. sodium chloride, glycerin, sorbitol, glucose etc. ), in the form of aqueous injectables, using conventional methods, or by suspending or emulsifying the active ingredient in a vegetable oil (e.g. olive oil, sesame oil, peanut oil, cottonseed oil, corn oil, etc. ) and propylene glycol to form an oil based injection preparation. An oral formulation can be prepared by tableting a compound of the invention together with a suitable excipient (e.g. lactose, sucrose, starch, etc. ), disintegrating substances (e.g. starch, in calcium eglan, etc. ), with a file (e.g. starch, acacia, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, etc. ) a slippery substance (e.g. talc, magnesium stearate, polyethylene glycol 6000, etc. ) and then by coating with a generally known method to mask the taste, create an outer skin or obtain the effect of prolonged action. Such a coating substance can be, for example, hydroxypropyl methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropyl cellulose methylphthalate, acetate succinate hydroxymethylcellulose (Germany), methudragacrylate, copolymer, Rohmeudragacrylate, copolymer, Rohmeudragacrylate, . titanium oxide, red oxide, etc. ). The compound according to the invention can also be used as a solid, semi-solid or liquid skin preparation. For example the solid skin preparation may be the compound of the invention as such or in admixture with an excipient (e.g. glycol, mannitol, starch, microcrystalline cellulose, etc. ), a thickening agent (e.g. natural gums, cellulose derivatives, acrylic acid polymers, etc. ), which then turns into a powder composition. The cutaneous semi-formulated preparation can be prepared in a conventional manner in the form of an aqueous or an oil-based or greasy gel. A dermal liquid preparation may be prepared by the method used in the preparation of an injectable preparation or analogous to the preparation of an oil-based form or an aqueous suspension. The solid, semi-solid or liquid skin preparation may be suitably supplemented with a pH modifier (e.g. egolic acid water, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc. ), an antiseptic (e.g. p-oxybenzoate, chlorobutanol, benzalkonium chloride etc. ) etc. . Typically petroleum or lanolin is used as the base formulation. To obtain the cream, about 0.1 to 100 mg of the compound according to the invention are used per 1 g of this preparation. The compound according to the invention may also be formulated in the form of a solid or semi-solid or liquid oil-based or water-based suppository. Oil-based suppository bases may suitably be e.g. sutured fat glyceride (eg. cocoa butter, Witepsol (Dynamite Nobel), etc. ), moderate fatty acid (e.g. Myglyol (Dynamite Nobel), etc. ) or vegetable oil (e.g. sesame oil, soybean oil, linseed oil, etc. ) etc. The water base can be e.g. polyethylene glycol or propylene glycol and aqueous gel bases may be e.g. natural rubber, cellulose derivatives, derivatives of vinyl and acrylic polymers, etc. While the dose of the compound of the invention may vary with the age, weight, and condition of the patient, dosage form, method and duration of treatment, it may, for example, be generally about 0.01 to about 1000 mg / kg, preferably about 0.01 to about 100 mg / kg, more preferably about 0.1 to about 100 mg / kg, most preferably about 0.1 to about 50 mg / kg, and especially about 1.5 to about 30 mg / kg per day in a patient suffering from sepsis (adults weighing about 60 kg), the daily dose being administered orally or parenterally at one time or in portions throughout the day. It is clear that a lower daily dose may be sufficient or an increase in dose may be required as this may vary depending on the various factors discussed above. Another object of the invention is the use of a derivative of formula I, II, III, IV or V, or a pharmaceutically acceptable salt thereof, respectively, in the manufacture of a medicament for the prevention or treatment of a cardiac disease, an autoimmune disease or septic shock. The invention further relates to pharmaceutical compositions containing, as active substances, derivatives of the compounds of formula I, II, III, IV or V, respectively, or their pharmaceutically acceptable salts, for use as a medicament for the prevention or treatment of a disease requiring the inhibition of nitric oxide production and / or cytokines. Preferably, these compositions are used to prevent or treat a cardiac disease, autoimmune disease or septic shock. Since the compounds according to the invention have low toxicity, inhibit the production of nitric oxide (NO) and inhibit the production of inflammatory cytokines such as TNF-α, IL-1 and IL-6, they are useful as a therapeutic and / or prophylactic agent in mammals (e.g. cats, cattle, dogs, horses, goats, dogs, humans, etc. ) against heart diseases, autoimmune diseases, inflammatory diseases, diseases of the central nervous system, infectious diseases, sepsis, septic shock, including sepsis, endotoxic shock, exotoxic shock, heart failure, shock, hypotension, rheumatoid arthritis, osteoarthritis, gastritis, ulcerative colitis, peptic ulcer, stress-inducing gastric ulcer, Crohn's disease, autoimmune disease, tissue posttransplantation failure and transplant rejection, reperfusion failure after ischaemia, acute vascular embolism, shock to asogenous vascular embolism (disseminated intravascular coagulation (DIC), etc. ), ischemic brain disorders, arteriosclerosis, paroxysmal anemia, Fanconi anemia, sickle cell anemia, pancreatitis, nephrotic syndrome, nephritis, kidney failure, insulin-dependent diabetes mellitus, insulin-induced diabetes, porphyroidism acute intermittent, alcoholism, Parkinson's disease, chronic leukemia, acute leukemia, tumors, myeloma, side effects of anti-cancer drugs, respiratory distress syndrome in children and adults, pulmonary emphysema, epilepsy, Alzheimer's disease, multiple sclerosis hay, vitamin E deficiency, aging, sunburn, muscular dystrophy, myocarditis, cardiomyopathy, myocardial infarction, sequelae of myocardial infarction, osteoporosis, pneumonia, atheritis, psoriasis , pain, smoke, flu infection, malaria, human immunodeficiency virus (HIV) infection, radiation failure, burn, the effectiveness of in vitro icing, hypercalcemia, tonic spondylitis, osteopenia, Behcet's bone disease, osteomalacia, fracture, acute bacterial meningitis, Helicobactor pylori infection, invasive staphylococcal infection, trichomic tuberculosis, mycosis , herpes simplex virus infection PL 203 663 B1 23, varicella-herpes zoster virus infection, human papillomavirus infection, acute viral encephalitis, encephalitis, asthma, atopic dermatitis, allergic rhinitis, reflux oesophagitis, fever epilepsy, hypercholesterolemia, hyperglyceridemia, hyperlipidemia, diabetic complications, diabetic kidney disease, diabetic neuropathy, diabetic retinopathy, gout, stomach atony, hemorrhoids, systemic lupus, spinal cord injury, insomnia, schizophrenia, epilepsy, epilepsy sci, liver failure, unstable coronary artery disease, valvular disease, dialysis-induced thrombocytopenia for, acute ischemic stroke, acute cerebral thrombosis, cancer metastasis, urinary bladder cancer, breast cancer, cervical cancer, colon cancer, gastric cancer, ovarian cancer, prostate cancer, small cell lung cancer, non-small cell lung cancer slippery melanoma, Hodgkin's disease, non-Hodgkin's lymphomas, etc. The compound of the invention (laa) or compound (s) is administered safely to humans as such or in admixture with suitable pharmacologically acceptable carriers, excipients and diluents, in dosage forms such as an oral formulation (e.g. powder, granule, tablet, capsule etc. ), parenteral preparation (e.g. injection preparation, skin preparation (e.g. intranasal preparation, intradermal preparation, etc. ), suppositories (e.g. rectal and vaginal suppositories, etc. ) as well as with other oral or parenteral pharmaceutical compositions. Each of these preparations can be prepared by any generally known method which is usually used for the preparation of a pharmaceutical preparation. The amount of a compound according to the invention (laa) or compound (le) that may be incorporated into the formulation may vary depending on the dosage form and is preferably about 10 to 95% by weight in the form described herein. above the oral formulation and about 0.001 to about 95% by weight for the parenteral formulation described above. For example the injectable preparation may be prepared by mixing a compound of the invention (laa) or compound (le) together with a solubilizing agent (e.g. ß-cyclodextrin, etc. ), dispersant (e.g. Tween 80 (Atlaspowder USA), HC060 (Nikko Chemicals), carboxymethyl cellulose, sodium alginate, etc. ), a preservative (e.g. methylparaben, propylparaben, benzyl alcohol, chlorobutanol etc. ), isotonic agent (e.g. sodium chloride, glycerin, sorbitol, glucose etc. ), in the form of an aqueous injection preparation using conventional methods, or by suspending or emulsifying the active ingredient in a vegetable oil (e.g. olive oil, sesame oil, peanut oil, cottonseed oil, corn oil, etc. ) and propylene glycol to form an oil based injection preparation. The oral preparation can be prepared by tabletting a compound of the invention (laa) or (le) together with an excipient (e.g. lactose, sucrose, starch, etc. ), disintegrating substance (eg. starch, in calcium eglan, etc. ), with a file (e.g. starch, acacia, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, etc. ) a slippery substance (e.g. talc, magnesium stearate, polyethylene glycol 6000, etc. ) and then by coating with a generally known method in order to mask the taste, create an outer coating or obtain a loose-action effect. Such a coating substance can be, for example, hydroxypropyl methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropyl cellulose methylphthalate, acetate succinylhydroxymethylcellulose, (Rohmeudragrylate, acrylate, methylacrylate, methacrylate, methacrylate, copolymer, acrylate, methacrylate, copolymer, acrylic acid, acrylic, copolymer) titanium oxide, red oxide, etc. ). The compound of the invention (laa) or the compound (s) may also be used as a solid, semi-solid or liquid skin preparation. For example the solid skin preparation may be a compound of the invention (laa) or a compound (le) as such or in admixture with an excipient (e.g. glycol, mannitol, starch, microcrystalline cellulose, etc. ), a thickening agent (e.g. natural gums, cellulose derivatives, acrylic acid polymers, etc. ), which then turns into a powder composition. The cutaneous semi-formulated preparation can be prepared in a standard manner in the form of an aqueous or an oil-based or greasy gel. A dermal liquid preparation may be prepared by the method used in the preparation of an injectable preparation or analogous to that of an oil-based form or an aqueous suspension. The solid, semi-solid or liquid skin preparation may be suitably supplemented with a pH modifier (e.g. egolic acid water, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc. ), an antiseptic (e.g. p-oxybenzoate, chlorobutanol, benzalkonium chloride etc. ) etc. . Typically petroleum or lanolin is used as the base formulation. To prepare the mask, about 0.1 to 100 mg of the compound according to the invention (laa) or compound (le) are used per 1 g of this preparation. The compound according to the invention (laa) or the compound (s) may also be formulated in the form of a solid or semi-solid or liquid oil-based or water-based suppository. The oil-based suppository bases may suitably be e.g. sutured fat glyceride (eg. cocoa butter, Witepsol (Dy- namit Nobel), etc. ), moderate fatty acid (e.g. Myglyol (Dynamite Nobel), etc. ) or vegetable oil (e.g. sesame oil, soybean oil, linseed oil, etc. ) etc. The water base can be e.g. polyethylene glycol or propylene glycol and aqueous gel bases may be e.g. natural rubber, cellulose derivatives, derivatives of vinyl and acrylic polymers, etc. While the dose of a compound of the invention (laa) or compound (le) may vary depending on the age, weight and condition of the patient, the dosage form, method and duration of treatment, it may, for example, be The toll is generally about 0.01 to about 1000 mg / kg, preferably about 0.01 to about 100 mg / kg, more preferably about 0.1 to about 100 mg / kg, most preferably about 0.1 to about 50 mg / kg, and in particular about 1.5 to about 30 mg / kg per day in a patient suffering from sepsis (adults weighing about 60 kg), the daily dose being the orally or parenterally once or in portions throughout the day. It is clear that a lower daily dose may be sufficient or an increase in the dose may be required as this may vary depending on the various factors discussed above. Best Mode for Carrying Out the Invention The present invention is further described with reference to Reference Examples, Preparation Examples, and Test Parts, which do not limit the scope of the invention. 1H NMR spectrum was performed using a Varian Gemini 200 spectrometer (200 MHz) using tetramethylsilane as an internal standard and all d values are expressed in ppm. The numbers in parentheses when a solvent mixture is used denote the volume ratio by volume of the ingredients in the mixture. A% means a% by weight, unless otherwise specified. The ratio of the solvents in the silica gel chromatography is the volume of the mixed solvents. A more polar diastereoisomer is a diastereoisomer with a lower Rf value as determined by the normal phase thin layer chromatography method under the same conditions (e.g. using ethyl acetate / hexane as eluent) in which the less polar diastereoisomer is the diastereoisomer with the higher Rf value (with such determination). The meanings of the abbreviations used in the examples are as follows: s: singlet d: doublet: t: triplet q: quartet DD: double doublet tt: triple triplet m: multiplet br: wide J: coupling constant Exemplary Reference example 1 Tetrahydrate Sodium peroxyborate (22.3 g) was mixed with acetic acid (120 ml) and heated to 50 to 55 ° C and then a solution of ethyl 2-mercapto-1-cyclohexene-1 carboxylate (9) was added dropwise over 2 hours. 0.0 g) in acetic acid (15 mL). The mixture was stirred at 50 to 55 ° C for 3 hours and then from 80 to 85 ° C for 5 hours and concentrated under reduced pressure. The residue was combined with acetonitrile (200 ml) and stirred at room temperature for 3 hours, and the resultant insolubles were filtered off. The insoluble matter was washed with acetonitrile (50 ml), and the filtrate and washing liquors were combined and concentrated under reduced pressure and the resulting residue was dissolved in acetonitrile (150 ml) and stirred at room temperature for 2 hours. The resulting insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The residue was combined with diisopropyl ether (300 ml) and the powder that precipitated was isolated by filtration to give ethyl 2-sulfo-1-cyclohexene-1 carboxylate as a white powder (18.8 g) containing inorganic substances. 1 H-NMR (DMSO-d 6) d: 1.17 (3H, t, J = 7 Hz), 1.53 (4H, br), 2.08-2.09 (2H, m), 2.22 -2.24 (2H, m), 3.99 (2H, q, J = 7Hz). Reference Example 2 Sodium peroxyborate tetrahydrate (74.3 g) was mixed with acetic acid (400 ml) and heated to 50 to 55 ° C and then an ethyl 2-mercapto-1-cyclohexene-1 carboxylate solution (30.0 g) was added. in acetic acid (50 ml) dropwise over 2 hours. The mixture was stirred at 50 to 55 ° C for 3 hours and then from 80 to 85 ° C for 5 hours and concentrated under reduced pressure. The residue was combined with acetonitrile (660 ml) and stirred at room temperature for 1 hour and the resultant insoluble matter was filtered off. The insoluble matter was washed with acetonitrile (50 ml), the filtrate and washing liquors were combined and concentrated under reduced pressure then obtained, and the residue was dissolved in acetonitrile (500 ml) and stirred at room temperature for 2 hours. The resulting insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The remaining residue was combined with diisopropyl ether (1000 ml) and the powder which had precipitated was isolated by filtration to give ethyl 2-sulfo-1-cyclohexene-1 carboxylate as a white powder (55 g) containing inorganic substances. . The whole was treated with thionyl chloride (150 ml), added dropwise at 0 ° C over 1 hour and then stirred for 20 hours at 80 to 85 ° C. The mixture was evaporated in vacuo to dryness and the residue was partitioned between ethyl acetate (300 ml) and diluted with brine (400 ml) and the aqueous layer was extracted with ethyl acetate (200 ml). The ethyl acetate layers were combined and washed with saturated brine (200 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was purified by flash chromatography on a silica gel column (eluent: ethyl acetate / hexane = 1/8 - ethyl acetate / hexane = 1/5) to give 2- carboxylate. chlorosulfonyl-1-cyclohexene-1-ethyl (21.5 g) as yellow crystals. 1 H-NMR (CDCl 3) d: 1.38 (3H, t, J = 7.0 Hz), 1.70-1.89 (4H, m), 2.52-2.67 (4H, m) , 4.30 (2H, q, J = 7.0Hz). Calculated values (%) for C 9 H 13 C 10 4 S: C, 42.77; H-5.18 Found (%): C-42.73, H-5.15 Melting Point 31.5 to 32.5 ° C Reference Example 3 Sodium Peroxyborate Tetrahydrate (10.6 g) was mixed with acetic acid (57 ml ) and heated from 50 to 55 ° C, and then a solution of ethyl 2-mercapto-1-cyclopenthenol carboxylate (3.9 g), synthesized according to Tetrahedron, Vol 30, p. 3753 (1974)) in acetic acid (7 ml) for 2 hours. The mixture was stirred at 50 to 55 ° C for 3 hours and then from 80 to 85 ° C for 5 hours and concentrated under reduced pressure. The residue was combined with acetonitrile (100 ml) and stirred at room temperature for 12 hours, and the resultant insoluble matter was filtered off. The insoluble matter was washed with acetonitrile (10 ml), the filtrate and washing liquors were combined and concentrated in vacuo to give and the residue was dissolved in acetonitrile (70 ml) and stirred at room temperature for 2 hours. The resulting insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The residue was combined with diisopropyl ether (20 ml) and the pellets which were precipitated by filtration were 2-sulfo-1-cyclopentene-1-ethyl carboxylate, as a white powder (7.8 g) containing the substance - inorganic. This compound (1.0 g) was dissolved in thionyl chloride (3 ml) and then stirred at 80 to 90 ° C for 15 hours. The mixture was evaporated in vacuo to dryness and the residues dissolved in ethyl acetate (50 ml). The resulting aqueous solution was washed successively with water (50 ml) and saturated brine (50 ml) and then dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was purified by flash chromatography on a silica gel column (eluent: ethyl acetate / hexane = 1/5) to give ethyl 2-chlorosulfonyl-1-cyclopentene-1-carboxylate (153.7 mg) as yellow oil. 1 H-NMR (CDCl 3) d: 1.35 (3H, t, J = 7.0Hz), 2.18 (2H, quintet, J = 8.0Hz), 2.92-3.08 (4H, m), 4.33 (2H, q, J = 7.0Hz). Reference Example 4 Sodium peroxyborate tetrahydrate (6.8 g) was mixed with acetic acid (37 ml) and heated to 50 to 55 ° C and then 2-mercapto-1-cycloheptene-1-ethyl carboxylate (2-mercapto-1-cycloheptene-1-carboxylate) was added dropwise over 1 hour ( 3.0 g, synthesized according to Tetrahedron, Vol.30, p. 3753 (1974)) in acetic acid (15 ml). The mixture was stirred at 50 to 55 ° C for 3 hours and then from 80 to 85 ° C for 5 hours and concentrated under reduced pressure. The remaining residue was combined with acetonitrile (100 ml) and stirred at room temperature for 3 hours, and the resultant insoluble matter was filtered off. The insoluble matter was washed with acetonitrile (10 ml), the filtrate and washing liquors were combined and concentrated in vacuo to give the result and the residue was dissolved in acetonitrile (70 ml) and then stirred at room temperature for 1 hour. The resulting insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The residue was combined with diisopropyl ether (100 ml) and the granules, which were precipitated by filtering onto ethyl 2-sulfo-1-cycloheptene-1 carboxylate as a white powder (3.4 g), contain using inorganic substances. This compound (1.5 g) was dissolved in thionyl chloride (4 ml) and then stirred at 80 to 90 ° C for 15 hours. The mixture was evaporated in vacuo to dryness and the residues dissolved in ethyl acetate (30 ml). The resulting solution was washed with saturated brine (30 mL × 2) and then dried over anhydrous sodium sulfate. The solvent was evaporated and the resulting residue was purified by flash chromatography on a silica gel column (eluent: ethyl acetate / hexane = 1/8) to give ethyl 2-chlorosulfonyl-1-cycloheptene-1 carboxylate (590 mg) in the form of brown oil. 1 H-NMR (CDCl 3) d: 1.34 (3H, t, J = 7.4Hz), 1.60-2.00 (6H, m), 2.40-2.90 (4H, m) . 4.29 (2H, q, J = 7.4Hz). Reference example 5 A solution of 6- [N- (4-chloro-2-fluorophenyl) sulfamoyl] -1-cyclohexene-1-ethyl carboxylate obtained according to the recipe of example 1 (compound 1, 210 mg) in acetonitrile (29 ml) was mixed with a 1 N aqueous sodium hydroxide solution (29 ml) and the mixture was stirred at 55 ° C for 12 hours. The mixture was concentrated under reduced pressure and the residues were purified on a CHP-20P column by column chromatography (eluent: water - methanol / water = 1/1). The solution after passing through the column was concentrated under reduced pressure and the residue e was dissolved in water (5 ml) and lyophilized to give 6- [N- (4-chloro-2-fluorophenyl) sulfamoyl] -1-cyclohexene carboxylate. 1 sodium (43 mg) as a white powder. 1 H-NMR (D 2 O) d: 1.65-2.40 (6H, m), 4.55 (1H, d, J = 3.0Hz), 6.86 (1H, t, J = 3 , 4Hz), 7.19-7.33 (2H, m), 7.50 (1H, t, J = 9.0Hz). Calculated values (%) for C 13 H 12 ClFNO 4 SNa • H 2 O: C-41.78; H, 3.78; N, 3.75 Found (%): C, 41.52; H-3.55; N-3.84 SIMS: 356 (MH +) Reference example 6 2,4-Difluoronitrobenzene (8.0 g) was dissolved in N, N-dimethylformamide (110 ml) and the solution was mixed with 1H-1,2,4-triazole (3.47 g) and potassium carbonate (6.95 g) and the mixture was stirred under nitrogen at 70 ° C for 20 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate and the ethyl acetate layer was combined and washed 5 times with water, then saturated brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1: 1.3). The desired fraction was concentrated under reduced pressure and the residues were crystallized from a mixture of ethyl acetate and diisopropyl ether to give 1- (3-fluoro-4-nitrophenyl) -1H-1,2,4-triazole (5 29 g) in the form of yellow powder crystals. 1 H-NMR (CDCl 3) d: 7.32-7.42 (2H, m), 8.13 (1H, dd, J = 9.8Hz, 5.0Hz), 8.15 (1H, s) , 8.43 (IH, s). Calculated values (%) for C 8 H 5 FN 4 O 2: C, 46.16; H-2.42; N, 26.92% Found: C, 45.98; H, 2.43; N, 26.85 Melting point; 90 to 91 ° C. Reference Example 7 1- (3-Fluoro-4-nitrophenyl) -1H-1,2,4-triazole (3.06 g) was dissolved in ethanol (100 ml) and mixed with 10% Pd / C ( 50% water, 612 mg) and then stirred under a hydrogen atmosphere at room temperature for 1 hour e. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate, and the resulting solution was washed successively with water and saturated brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residues were purified by silica gel column chromatography (ethyl acetate / hexane = 1: 2). The desired fraction was concentrated under reduced pressure, and the residues were crystallized from a mixture of ethyl acetate and diisopropyl ether to give 1- (4-amino-3-fluorophenyl) -1H- -1,2,4-triazole (1.68 g ) in the form of yellow crystals in the form of a powder. 1 H-NMR (CDCl 3) d: 4.41 (2H, br), 6.78-6.85 (1H, m), 6.96-7.05 (2H, m), 8.16 (1H , s). 8.37 (IH, s). Calculated values (%) for C 8 H 7 FN 4: C, 53.93; H, 3.96; N, 31.45 Found (%): C, 54.07; H, 3.82; N-31.55 Melting point: 103 to 104 ° C. Reference example 8 Methyl 4-amino-3-chlorobenzoate (5.65 g; synthesized according to Synthesis, 1985, 669) was dissolved in tetrahydrofuran (112 ml) and mixed with the solution sodium hydrogen carbonate (7.67 g) in water (84.8 ml) and benzyl chloroformate (39.1 ml) and the mixture was stirred under nitrogen at room temperature for 22.5 hours. The reaction mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed three times with water and then twice with saturated brine. The ethyl acetate layers were dried over magnesium sulfate and then the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1: 7). The desired fraction was concentrated under reduced pressure and the residues crystallized from a mixture of ethyl acetate and diisopropyl ether to give methyl 4-benzyloxycarbonylamino-3-chlorobenzoate (7.51 g) as white crystals. 1 H-NMR (CDCl 3) d: 3.91 (3H, s), 5.25 (2H, s), 7.38-7.44 (6H, m), 7.95 (1H, dd, J = 8.8Hz, 2.0Hz), 8.06 (1H, d, J = 2.0Hz), 8.33 (1H, d, J = 8.8Hz). Calculated values (%) for C 16 H 14 ClNO 4: C, 60.10; H, 4.41; N, 4.38 Found (%): C, 60.21; H, 4.42; N-4.22 Melting point: 107.5 to 108.5 ° C Reference example 9 T-potassium butoxide (24.7 g) was dissolved in dimethylsulfoxide (221 ml) and mixed with methyl 4-benzyloxycarbonylamino-3-chlorobenzoate (4.52 g) and the mixture was stirred at room temperature for 25 minutes. The reaction mixture was poured into water (200 ml) which was then acidified with 1N hydrochloric acid (225 ml) and then extracted with ethyl acetate. The ethyl acetate layers were washed successively with water and saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residues were purified by silica gel column chromatography (ethyl acetate / hexane = 2: 5). The desired fraction was concentrated under reduced pressure to give 4-benzyloxycarbonylamino-3-chlorobenzoic acid (2.47 g) as a white powder. 1 H-NMR (d 6 -DMSO) d: 3.34 (1H, br), 5.20 (2H, s), 7.34-7.47 (5H, m), 7.86 (1H, s ), 7.87 (IH, s), 7.93 (IH, s), 9.40 (IH, s). Calculated values (%) for C 15 H 12 CINO 4: C, 58.93; H, 3.96; N, 4.58 Found (%): C, 58.85; H, 3.93; N-4.55 Melting point: 181.5 to 182.5 ° C Reference example 10 4-Benzyloxycarbonylamino-3-chlorobenzoic acid (0.80 g) was dissolved in N, N-dimethylformamide (24.0 ml) and mixed at room temperature with t-butyl glycinate (0.44 g) and triethylamine (0.77 ml). Diethyl cyanophosphate (0.43 ml) was added under ice-cooling, and the mixture was stirred under nitrogen at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layers were separated and the aqueous layer was extracted with ethyl acetate. The ethyl acetate layers were combined and washed three times with water, then twice with saturated brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residues e were crystallized from a mixture of ethyl acetate and diisopropyl ether to give N- (4-benzyloxycarbonylamino-3-chlorobenzoyl) t-butyl glycinate (0.93 g) as white crystals . 1 H-NMR (CDCl 3) d: 1.51 (9H, s), 4.12 (2H, d, J = 5.0Hz), 5.24 (2H, s), 6.58 (1H, t , J = 5.0Hz), 7.37-7.45 (6H, m), 7.68 (1H, dd, J = 8.6Hz, 2.0Hz), 7.89 (1H, d, J = 2.0Hz), 8.32 (1H, d, J = 8.6Hz). Calculated values (%) for C 21 H 23 CIN 2 O 5: C, 60.22; H-5.53; N, 6.69 Found (%): C, 60.27; H-5.50; N-6.69 Melting point: 163 to 164 ° C reference example 11 N- (4-benzyloxycarbonylamino-3-chlorobenzoyl) t-butyl glycinate (0.80 g) was dissolved in tetrahydrofuran (30 ml) and then mixed with 10% Pd / C (50% water, 160 mg) was then stirred under a hydrogen atmosphere at room temperature for 1.5 hours. The catalyst was filtered off and the filtrate was diluted with ethyl acetate and washed three times with water and twice with saturated brine. The ethyl acetate layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1: 1). The desired fraction was concentrated under reduced pressure and the residue was crystallized from a mixture of diisopropyl ether and hexane to give N- (4-amino-3-chlorobenzoyl) t-butyl glycinate (0.49 g) as white crystal lows. 1 H-NMR (CDCl 3) d: 1.50 (9H, s), 4.11 (2H, d, J = 5.0Hz), 4.38 (2H, s), 6, 47 (1H, m), 6.75 (1H, d, J = 8.4Hz), 7.54 (1H, dd, J = 8.4Hz, 2.0Hz), 7.77 (1H, d, J = 2.0Hz). Calculated values (%) for C 13 H 17 ClNO 3: C, 54.84; H-6.02; N, 9.84 Found (%): C, 54.56; H, 5.85; N-9.54 Melting point: 116 to 117 ° C. Reference example 12 Solution of ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate prepared according to the recipe of example 3 (compound 3 2.5 g) in acetonitrile (288 ml) was mixed with a 1 N aqueous sodium hydroxide solution (228 ml) and the mixture was stirred at 55 ° C for 12 hours. The mixture was concentrated under reduced pressure and the residue was purified on a CHP-20P column by column chromatography (eluent: water - methanol / water = 1/1). The eluent was concentrated under reduced pressure and the residue e was dissolved in water (10 ml) and lyophilized to give sodium 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (0.50 g ) in the form of white crystals. 1 H-NMR (d 6 -DMSO) d: 1.50-1.65 (2H, m), 1.78-2.41 (4H, m), 4.13 (1H, d, J = 4Hz) , 6.88-6.98 (2H, m), 7.09-7.20 (1H, m), 7.42 (1H, dt, J = 9.0Hz, 6.2Hz). Calculated values (%) for C 13 H 12 F 2 NO 4 SNa • H 2 O: C-43.70; H-3.95; N, 3.92 Found (%): C, 44.17; H, 3.86; N-3.57 SIMS: 340 (MH +) Sodium 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (0.48 g) was dissolved in water (100 ml) and adjusted to pH 1 to 2 with 1 N HCl and then extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with water (100 mL × 2) and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was crystallized from diisopropyl ether to give 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylic acid (0.44 g) as white powdered crystals. 1 H-NMR (d 6 -DMSO) d: 1.56-1.78 (2H, m), 2.00-2.41 (4H, m), 4.31 (1H, d, J = 4, 2Hz), 7.08 (2H, br), 7.26-7.37 (1H, m), 7.44-7.56 (1H, m), 9.80 (1H, br), 12.38 (1H, br). Calculated values (%) for C 13 H 13 F 2 NO 4 S: C, 49.21; H-4.13; N, 4.41 Found (%): C, 49.47; H-4.16; N-4.62 SIMS: 317 (M +) P r z o d n i e s i e n i a 13 2-Oxo-5-phenylcyclohexaneethyl carboxylate (57.5 g) (synthesized according to Chemical & Pharmaceutical Bulletin, Vol 20, p. 277 (1972)) was subjected to the transformations described in Tetrahedron. Volume 30, pp. 3753 (1974) to give 2-mercapto-5-phenyl-1-cyclohexene-1-ethyl carboxylate (29.3 g) as light yellow powder crystals. 1 H-NMR (CDCl 3) d: 1.27 (3H, t, J = 7.2 Hz), 1.76-2.05 (2H, m), 2.28-2.91 (5H, m) , 4.10 (1H, s), 4.21 (2H, q, J = 7.2Hz), 7.19-7.38 (5H, m). Calculated values (%) for C 15 H 18 O 2 S: C, 68.67; H, 6.92 Found (%): C, 68.86; H-6.82. Reference Example 14 Sodium peroxyborate tetrahydrate (35.2 g) was mixed with acetic acid (200 ml) and heated to 50 to 55 ° C and then 2-mercapto-5-phenyl-1-cyclohexene carboxylate solution. 1 ethyl acetate synthesized by the method of Reference Example 13 (20 g) and 1 N acetic acid (200 ml) were added dropwise over 2 hours. The mixture was stirred at 50 to 55 ° C for 3 hours and then from 80 to 85 ° C for 5 hours and concentrated under reduced pressure. The residue was combined with acetonitrile (500 ml) and then stirred at room temperature for 1 hour and the resulting insoluble matter was filtered off. The insoluble matter was washed with acetonitrile (20 ml), and the filtrate and washing liquors were combined and concentrated under reduced pressure to give and the residue was dissolved in a mixture of acetonitrile (500 ml) and methanol (500 ml) and then stirred. at room temperature for 2 hours. The resulting insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was combined with diisopropyl ether (500 ml) and the granules which were precipitated by filtration gave the ethyl 5-phenyl-2-sulfo-1-cyclohexene-1-carboxylate as a white powder (40.4 g) acetic inorganic substances. This compound (10 g) was treated dropwise with thionyl chloride (30 ml) at 0 ° C for 1 hour and then stirred at 85 to 90 ° C for 7 hours. The solution was evaporated in vacuo to dryness and the residues were dissolved in ethyl acetate (50 ml). The resulting solution was washed successively with water (50 ml) and saturated brine (50 ml), and then dried over anhydrous sodium sulfate. The solvent was evaporated off to give a residue, which was purified by flash chromatography on a column packed with silica gel (eluent: ethyl acetate / hexane = 1/8) to give 2-chlorosulfonyl-5-phenyl-1-cyclohexene-1-ethyl carboxylate. (4.8 g) as light yellow crystals. 1 H-NMR (CDCl 3) d: 1.35 (3H, t, J = 7.4Hz), 1.85-2.02 (1H, m), 2.14-2.26 (1H, m) , 2.56-3.02 (5H, m), 4.31 (2H, q, J = 7.4Hz), 7.19-7.40 (5H, m). P r z y k l a d o d n i e s i e n i a 15 5-t-Butyl-2-oxocyclohexeneethyl carboxylate (50.7 g) [synthesized according to Collect. Czech. Chem. Commun. , 1976, 41, 2928] was subjected to the transformations described in Tetrahedron, vol. 30, pp. 3753 (1974) to give ethyl 5-t-butyl-2-mercapto-1-cyclohexene-1 carboxylate (39.6 g) as a yellow oil. 1 H-NMR (CDCl 3) d: 0.90 (9H, s), 1.22-1.34 (1H, m), 1.32 (3H, t, J = 7.2Hz), 1.75 -2.03 (3H, m), 2.40- 2.67 (3H, m), 3.91 (1H, s), 4.24 (2H, q, J = 7.2Hz). Calculated values (%) for C 13 H 22 O 2 S: C, 64.42; H, 9.15 Found (%): C, 64.47; H-9.29. Reference Example 16 Sodium peroxyborate tetrahydrate (38.2 g) was mixed with acetic acid (270 ml) and heated to 50 to 55 ° C and then a solution of 5-t-butyl-2-mercapto carboxylate. Ethyl 1-cyclohexene-1 (20.1 g), synthesized according to the method described in Reference Example 15, in acetic acid (31 ml), was added dropwise over 2 hours. The mixture was stirred at 50 to 55 ° C for 3 hours and then at 80 to 85 ° C for 7.5 hours and concentrated under reduced pressure. The residue was combined with acetonitrile (445 ml), then stirred at room temperature for 3.5 hours, and the resultant insoluble matter was filtered off. The insoluble matter was washed with acetonitrile (110 ml), the filtrate and washing liquors were combined and concentrated in vacuo to give the obtained residue dissolved in acetonitrile (320 ml) and then stirred at room temperature for 15 hours. The resulting insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The residue was combined with diisopropyl ether (250 ml) and the pellets which had precipitated were isolated by filtration and concentrated under reduced pressure to give ethyl 5-t-butyl-2-sulfo-1-cyclohexene-1-ethyl carboxylate in the form of yellow oil (17.6 g) containing inorganic substances. This compound (16.4 g) was treated dropwise with thionyl chloride (49.2 ml) at 0 ° C for 0.5 hours and then stirred at 80 to 90 ° C for 7 hours. The solution was evaporated in vacuo to dryness and the residue was partitioned between ethyl acetate (200 ml) and diluted brine (240 ml) and the aqueous layer was extracted with ethyl acetate (100 ml). The combined ethyl acetate layers were washed with saturated brine (120 ml) and then dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was purified by column chromatography over silica gel (eluent: ethyl acetate / hexane = 1/10), and the desired fraction was concentrated under reduced pressure. The residue was crystallized from hexane to give ethyl 5-t-butyl-2-chlorosulfonyl-1-cyclohexene-1-carboxylate (7.4 g) as white crystals. 1 H-NMR (CDCl 3) d: 0.92 (9H, s), 1.22-1.46 (2H, m), 1.36 (3H, t, J = 7.2Hz), 2.04 -2.35 (2H, m), 2.45-2.65 (2H, m), 2.79-2.92 (1H, m), 4.31 (2H, q, J = 7.2Hz) . Calculated values (%) for C 13 H 21 C 10 4 S: C, 50.56; H, 6.85% Found: C, 50.47; H-6.74 P r z y k l a d o d n i e s i e n i a 17 5,5-Dimethyl-2-oxocyclohexeneethyl carboxylate (31.2 g) [synthesized according to J. Org. Chem. , 1953, 18, 661] was subjected to the transformations described in Tetrahedron, Vol. 30, pp. 3753 (1974) to give ethyl 5,5-dimethyl-2-mercapto-1-cyclohexene-1-carboxylate (29.9 g) as a yellow oil. 1 H-NMR (CDCl 3) d: 0.95 (6H, s), 1.31 (3H, t, J = 7.0Hz), 1.43 (2H, t, J = 6.4Hz), 2 , 14 (2H, t, J = 2.0Hz), 2.45-2.55 (2H, m), 3.88 (1H, s), 4.22 (2H, q, J = 7.0Hz) . Calculated values (%) for C 11 H 18 C 2 S: C, 61.64; H, 8.47 Found (%): C, 61.40; H-8.68PL 203 663 B1 30 Reference Example 18 Sodium peroxyborate tetrahydrate (46.3 g) was mixed with acetic acid (270 ml) and heated to 50 to 55 ° C and then the 5,5-dimethyl carboxylate solution. Ethyl 2-mercapto-1-cyclohexene-1 (20.2 g), synthesized according to the method described in Reference Example 17, in acetic acid (30 ml) was added dropwise over 2 hours. The mixture was stirred at 50 to 55 ° C for 3 hours, then from 80 to 85 ° C for 8 hours, and concentrated under reduced pressure. The residue was combined with acetonitrile (450 ml), then stirred at room temperature for 4 hours, and the resultant insoluble matter was filtered off. The insoluble matter was washed with acetonitrile (120 ml), the filtrate and washing liquors were combined and concentrated under reduced pressure to give and the residue was dissolved in acetonitrile (330 ml) and then stirred at room temperature for 15 hours. The resulting insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The residue was combined with diisopropyl ether (300 ml) and the powder that was precipitated was isolated by filtration to give 5,5-dimethyl-2-sulfo-1-cyclohexene-1-ethyl carboxylate as an orange oil (26.5 g) containing inorganic substances. This compound (26.3 g) was dissolved in thionyl chloride (79 ml) and then stirred at 80 to 90 ° C for 7.5 hours. The solution was evaporated in vacuo to dryness and the residues were dissolved in ethyl acetate (150 ml). The solution thus obtained was combined with diluted brine (200 ml) and partitioned, and then the ethyl acetate layer was washed twice with saturated brine (100 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/8) to give 2-chlorosulfonyl-5,5-dimethyl-1-cyclohexene-1-carboxylate. ethyl (12.4 g) as a brown oil. 1 H-NMR (CDCl 3) d: 1.02 (6H, s), 1.34 (3H, t, J = 7.2Hz), 1.61 (2H, t, J = 6.6Hz), 2 , 31 (2H, t, J = 2.4Hz), 2.64-2.72 (2H, m), 4.30 (2H, q, J = 7.2Hz). Calculated values (%) for C 11 H 17 ClO 4 S: C, 47.06; H, 6.10. Found (%): C, 47.46; H-6.10. Example 1 Ethyl 2-sulfo-1-cyclohexene-1 carboxylate (7.11 g), obtained by the method a indicated in reference example 1, was dissolved in thionyl chloride (21.0 ml) and heated at reflux for 14 hours and then the reaction mixture was evaporated to dryness under reduced pressure. The remainder was subjected three times to the procedure of adding hexane (30 ml) followed by evaporation in vacuo to dryness to give ethyl 2-chlorosulfonyl-1-cyclohexene-1 carboxylate. The total was combined with ethyl acetate (20 mL) and the resulting mixture was added to a mixture consisting of 4-chloro-2-fluoroaniline (3.64 g), triethylamine (3.41 mL) and ethyl acetate (54 ml) and then stirred at room temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate (50 ml) and water (200 ml). The ethyl acetate layer was washed with dilute brine (100 mL × 3) and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The remaining residue was combined with diisopropyl ether (8 ml) and the crystals that precipitated were isolated by filtration. The crystals thus obtained were washed with ethyl acetate (8 ml) to give ethyl 6- [N- (4-chloro-2-fluorophenyl) sulfamoyl] -1-cyclohexene-1 carboxylate (compound 1; 1, 60 g) in the form of colorless needle-like crystals. After washing, the mother liquors were combined and chromatographed on silica gel (eluent: ethyl acetate / hexane = 1/5 → 1/4) and the solution after passing through the column was concentrated under reduced pressure and the residues were crystallized from a mixture of ethyl acetate. diisopropyl ether to give a second crop of compound 1 (1.41 g). 1H-NMR (DMSOd6) d: 1.10 (3H, t, J = 7.2Hz), 1.57-1.82 (2H, m), 1.98-2.44 (4H, m) , 4.02 (2H, q, J = 7.2Hz), 4.32 (1H, d, J = 4.4Hz), 7.12 (1H, t. J = 3.4 Hz), 7.23-7.31 (1H, m), 7.45-7.54 (2H, m), 10.04 (1H, s). Calculated values (%) for C 15 H 17 CIFINK 4 S: C, 49.79; H-4.74; N, 3.87 Found (%): C, 49.93; H, 4.72; N-4.09. Example 2 For a solution of ethyl 6- [N- (4-chloro-2-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (compound 1; 250 mg) obtained by method a according to example 1 , 1.60 g) in N, N-dimethylformamide (2.5 ml), methyl iodide (118 mg) was added in potassium carbonate (191 mg) and the mixture was stirred at room temperature for 1 hour e. The reaction mixture was diluted with ethyl acetate (30 ml), washed with water (30 ml × 2) and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate / hexane = 1/4) to give 6- [N- (4-chloro-2-fluorophenyl) -N-methylsulfamoyl] -1-cyclohexene carboxylate -1 ethyl (compound 2; 250 mg) as a colorless oil. 1 H-NMR (DMSO-d 6) d: 1.17 (3H, t, J = 7.2 Hz), 1.56-2.44 (6H, m), 3.19 (3H, s), 4 , 12 (2H, q, J = 7.2Hz), 4.64 (1H, d, J = 4.4Hz), 7.16 (1H, t, J = 3.6Hz), 7.33-7, 39 (1H, m), 7.54-7.62 (2H, m). Calculated values (%) for C 16 H 19 CIFNO 4 S: C, 51.13; H, 5.10; N, 3.73 Found (%): C, 50.91; H, 5.10; N-3.64. Example 3 2-sulfo-1-cyclohexene-1-ethyl carboxylate (2.0 g), prepared by the method a indicated in reference example 1, was dissolved in thionyl chloride (5.9 ml) and heated to a temperature of under reflux for 14 hours and then the reaction mixture was evaporated under reduced pressure to dryness. The remainder was subjected three times to the procedure of adding hexane (10 ml) followed by evaporation in vacuo to dryness to give ethyl 2-chlorosulfonyl-1-cyclohexene-1 carboxylate. The total was combined with ethyl acetate (15 ml) and the resulting mixture was added to a mixture consisting of 2,4-difluoroaniline (1.29 g), triethylamine (2.0 ml) and ethyl acetate (10 ml), cooled with ice and then stirred, cooled with ice for 30 minutes and then at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with dilute brine (150 ml × 3) and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The remainder was combined with diisopropyl ether (6 ml) and the crystals that precipitated were isolated by filtration to yield 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-ethyl carboxylate (compound 3; 0.61 g) as colorless needle-like crystals. 1 H-NMR (DMSO-d 6) d: 1.07 (3H, t, J = 7.2 Hz), 1.46-1.82 (2H, m), 1.97-2.50 (4H, m), 4.01 (2H, q, J = 7.2Hz), 4.28 (1H, d, J = 4.8Hz), 7.04-7.15 (2H, m), 7.29- 7.54 (2H, m), 9.86 (1H, br s). Calculated values (%) for C 15 H 17 F 2 NO 4 S: C-52.17; H, 4.96; N, 4.06 Found (%): C, 52.27; H, 4.84; N-3.98. Example 4 Ethyl 2-sulfo-1-cyclohexene-1 carboxylate (0.67 g), obtained by the method indicated in Reference Example 1, was dissolved in thionyl chloride (2.0 ml) and heated in at reflux for 8 hours, and then the reaction mixture was evaporated to dryness under reduced pressure. The procedure was performed three times, involving the addition of hexane (8 ml), followed by evaporation under reduced pressure to dryness to give ethyl 2-chlorosulfonyl-1-cyclohexene-1 carboxylate. Total sc was combined with ethyl acetate (5 ml) and the resulting mixture was added to a mixture consisting of 2,6-diisopropylaniline (0.89 g), triethylamine (0.70 ml) and ethyl acetate (8 ml). it was cooled with ice and then stirred, cooled with ice for 30 minutes and then at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate (20 ml) and washed with water (40 ml) and diluted with brine (40 ml × 3) and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by chromatography on silica gel (eluent: ethyl acetate / hexane = 1/20 → 1/9) to give 6- [N- (2,6-diisopropylphenyl) sulfamoyl] -1-cyclohexene-1-ethyl carboxylate ( compound 4, 0.12 g) as a colorless oil. 1 H-NMR (DMSO-d 6) d: 0.99 (3H, t, J = 7.2 Hz), 1.15 (12H, d, J = 6.6 Hz), 1.58-2.60 ( 6H, m), 3.39-3.52 (2H, m), 3.97 (2H, q, J = 7.2Hz), 4.38 (1H, d, J = 5.4Hz), 7, O 5 (1H, br), 7.15-7.31 (3H, m), 8.96 (1H, s). Example 5 Ethyl 2-sulfo-1-cyclohexene-1 carboxylate (1.0 g), obtained by the method a indicated in Reference Example 1, was dissolved in thionyl chloride (3.0 ml) and heated under reflux. reflux for 8 hours, and then the reaction mixture was evaporated under reduced pressure to dryness. The procedure was performed three times involving the addition of hexane (10 ml) followed by evaporation under reduced pressure to dryness to yield ethyl 2-chlorosulfonyl-1-cyclohexene-1 carboxylate. The total was combined with ethyl acetate (10 ml) and the resulting mixture was added to a mixture consisting of 4-nitroaniline (0.69 g), triethylamine (0.70 ml) and ethyl acetate (8 ml), ice-ice and then stirring, ice-cooling for 30 minutes and then at room temperature for 14 hours. The reaction mixture was diluted with ethyl acetate (60 ml) and washed with dilute brine (50 ml × 3) and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by chromatography on silica gel (eluent: ethyl acetate / hexane = 1/2) and then crystallized from diisopropyl ether to give 6- [N- (4-nitrophenyl) sulfamoyl] -1-cyclohexene carboxylate. 1 ethyl (compound 5; 90 mg) as light yellow powder in the form of a powder. 1 H-NMR (DMSO-d 6) d: 1.13 (3H, t, J = 7 Hz), 1.60-1.85 (2H, m), 1.96-2.46 (4H, m) , 3.90-4.16 (2H, m), 4.46 (1H, d, J = 5Hz), 7.21 (1H, t, J = 3Hz), 7.38 (2H, d, J = 9Hz), 8.22 (2H, d, J = 9Hz), 10.92 (1H, s). Calculated values (%) for C 15 H 18 N 2 O 6 S: C, 50.84; H, 5.12; N, 7.90 Found (%): C, 50.80; H, 4.99; N-7.93. Example 6 Ethyl 2-sulfo-1-cyclohexene-1 carboxylate (0.67 g), obtained by the method indicated in Reference Example 1, was dissolved in thionyl chloride (2.0 ml) and heated in at reflux for 8 hours and then the reaction mixture was evaporated under reduced pressure to dry weight. The procedure was performed three times involving the addition of hexane (10 ml) followed by evaporation under reduced pressure to dryness to yield 2-chlorosulfonyl-1-cyclohexene-1-ethyl carboxylate. The total mixture was combined with ethyl acetate (12 ml) and the resulting mixture was added to a mixture consisting of aniline (0.28 g), triethylamine (0.42 ml) and ethyl acetate (4 ml), cooled with ice. and then stirred, ice-cooled for 30 minutes and then at room temperature for 13 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (50 ml) and 0.2 N HCl (50 ml) and water (50 ml × 2) and dried over anhydrous magnesium sulfate and then with solvent. distilled. The rest was purified by silica gel chromatography (eluent: ethyl acetate / hexane = 1/4) and the first solution was concentrated under reduced pressure after passing through the column and the rest was purified by octadecyl column chromatography ( ODS) (eluent: methanol / water = 7/3). The solution after passing through the column was concentrated under reduced pressure to precipitate crystals which were collected by filtration to give ethyl 2- (N-phenylsulfamoyl) -1-cyclohexene-1-carboxylate (compound 7; 37 mg) in the form of colorless powdered crystals. The second solution, after passing through the columns, was also concentrated under reduced pressure and the residue obtained was purified by chromatography on an ODS column (eluent: methanol / water = 7/3). The solution after passing through the column was concentrated under reduced pressure and the residue was crystallized from a methanol-water mixture to give ethyl 6- (N-phenylsulfamoyl) -1-cyclohexene-1-carboxylate (compound 6; 56 mg) as colorless needle-like crystals. Compound 6: 1 H-NMR (DMSO-d 6) d: 1.14 (3H, t, J = 7.2Hz), 1.55-1.74 (2H, m), 1.98-2, 42 (4H, m), 3.97-4.12 (2H, m), 4.32 (1H, d, J = 4.8Hz), 7.02-7.35 (6H, m), 10. 03 (1H, brs). Calculated values (%) for C 15 H 19 NO 4 S: C, 58.23; H, 6.19; N, 4.53 Found (%): C, 58.28; H, 6.19; N-4.55 Compound 7: 1 H-NMR (DMSO-d 6) d: 1.23 (3H, t, J = 7 Hz), 1.54 (4H, br), 2.25 (4H, br ), 4.14 (2H, q, J = 7 Hz), 7.02-7.32 (5H, m), 10.13 (1H, br s). Calculated values (%) for C 15 H 19 NO 4 S: C, 58.23; H, 6.19; N, 4.53 Found (%): C, 57.94; H, 6.10; N-4.52 Ethyl 2-sulfo-1-cyclohexene-1 carboxylate (2.0 g), prepared by the method a indicated in Reference Example 1, was dissolved in thionyl chloride (5.0 ml) and heated under reflux. for 14 hours and then the reaction mixture was evaporated to dryness under reduced pressure. The procedure was performed three times involving the addition of hexane (10 ml) followed by evaporation under reduced pressure to dryness to yield ethyl 2-chlorosulfonyl-1-cyclohexene-1 carboxylate. The total was combined with ethyl acetate (30 ml) and washed with dilute brine (30 ml × 2) and saturated brine (20 ml) and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting oil was mixed together with a solution of 4-chloro-2-fluoroaniline (0.55 g) in N, N-dimethylformamide (5 ml) at room temperature for 18 hours. The reaction mixture was combined with ice-water (100 ml) and ethyl acetate (100 ml) and partitioned. The ethyl acetate layer was washed with water (80 ml × 2) and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate / hexane = 1/4) and crystallized from diisopropyl ether to give 2- [N- (4-chloro-2-fluorophenyl) sulfamoyl] -1 carboxylate. -cyclohexene-1-ethyl (compound 9; 44 mg) as colorless powdered crystals. 1 H-NMR (DMSO-d 6) d: 1.06 (3H, t, J = 7.2 Hz), 1.62 (4H, br), 2.25 (2H, br), 2.39 (2H, br), 3.95 (2H, q, J = 7.2Hz), 7.23-7.37 (2H, m), 7.47-7.52 (1H, m), 10.11 (1H, s). Calculated values (%) for C 15 H 17 CIFNO 4 S: C, 49.79; H-4.74; N, 3.87 Found (%): C, 49.84; H, 4.76; N-3.92. Example 8 Ethyl 2-sulfo-1-cyclohexene-1 carboxylate (0.67 g), obtained by the method a indicated in Reference Example 1, was dissolved in thionyl chloride (2.0 ml) and heated at reflux for 8 hours and then the reaction mixture was evaporated to dryness under reduced pressure. The procedure was performed three times, involving the addition of hexane (8 ml), followed by evaporation under reduced pressure to dryness to give ethyl 2-chlorosulfonyl-1-cyclohexene-1 carboxylate. The whole mixture was combined with ethyl acetate (10 ml) and the resulting mixture was added to a mixture consisting of 4-methoxyaniline (0.37 g), triethylamine (0.42 ml) and ethyl acetate (4 ml). it was cooled with ice and then stirred, cooled with ice for 30 minutes and then at room temperature for 13 hours. The reaction mixture was diluted with ethyl acetate (60 ml) and washed with dilute brine (80 ml), 10% aqueous phosphoric acid (50 ml) and dilute brine (50 ml × 2), and dried over anhydrous magnesium sulfate and then the solvent was distilled off. The residue was purified by chromatography on silica gel (eluent: ethyl acetate / hexane = 1/2) and the solution after passing through the column was concentrated to dryness and the residue was crystallized from ethyl acetate-diisopropyl ether to give 2- (4-methoxyphenyl) -4,5,6,7-tetrahydro-1,2-benzisothiazol-3 (2H) -one 1,1-dioxide (compound 67, 40 mg) as colorless needles like crystals . The mother liquors were concentrated and purified by column chromatography on an ODS column (eluent: methanol / water = 7/3) and then the solution passed through the column was concentrated under reduced pressure to give 2- [N- ( 4-methoxyphenyl) sulfamoyl] -1-cyclohexene-1-ethyl (compound 8; 15 mg) as a colorless powder. Compound 8: 1H-NMR (DMSO-d6) d: 1.18 (3H, t, J = 7.0Hz), 1.54, 1.56 (4H, br), 2.25 (4H, br). 3.72 (3H, s), 4.08 (2H, q, J = 7.0Hz), 6.86 (2H, d, J = 8Hz), 7.07 (2H, d, J = 8Hz), 9.79 (1H, br s). Compound 67: 1 H-NMR (CDCl 3) d: 1.70-1.88 (4H, m), 2.41-2.60 (4H, m), 3.82 (3H, s), 7 . 11 (2H, d, J = 9.0 Hz), 7.31 (2H, d, J = 9.0 Hz). Calculated values (%) for C 14 H 15 NO 4 S: C, 57.32; H, 5.15; N, 4.77 Found (%): C, 57.41; H-5.01; N-4.78. Example 9 Ethyl 2-sulfo-1-cyclohexene-1 carboxylate (0.83 g), obtained from the method indicated in reference example 1, was dissolved in thionyl chloride (2.4 ml) and heated in at reflux for 8 hours, and then the reaction mixture was evaporated to dryness under reduced pressure. The procedure was performed three times involving the addition of hexane (10 ml) followed by evaporation under reduced pressure to dryness to yield ethyl 2-chlorosulfonyl-1-cyclohexene-1 carboxylate. The total mixture was combined with ethyl acetate (10 ml) and the resulting mixture was added to a mixture consisting of 2-fluoroaniline (0.40 g), triethylamine (0.50 ml) and ethyl acetate (5 ml). , cooled with ice and then stirred, cooled with ice for 30 minutes and then at room temperature for 14 hours. The reaction mixture was diluted with ethyl acetate (30 ml) and washed with water (30 ml). The ethyl acetate layers were washed with 0.5 N HCl (30 ml) and water (30 ml × 2), and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate / hexane = 1/4) and then crystallized from diisopropyl ether to give 6- [N- (2-fluorophenyl) sulfamoyl] -1-cyclohexene carboxylate. 1 ethyl (compound 10; 303 mg) in the form of colorless needle-like crystals. 1 H-NMR (DMSO-d 6) d: 1.07 (3H, t, J = 7.2 Hz), 1.58-1.82 (2H, m), 2.05-2.46 (4H, m), 4.01 (2H, q, J = 7.2Hz), 4.32 (1H, d, J = 4.6Hz), 7.09-7.32 (4H, m), 7.44- 7.54 (1H, m), 9.91 (1H, br s). Calculated values (%) for C 15 H 18 FNO 4 S: C-55.03; H-5.54; N, 4.28 Found (%): C, 55.09; H, 5.44; N-4.33. Example 10 2-sulfo-1-cyclohexene-1-ethyl carboxylate (1.0 g), obtained by the method a indicated in reference example 1, was dissolved in thionyl chloride (3.0 ml) and heated to a temperature of It was refluxed for 14 hours and then the reaction mixture was evaporated to dryness under reduced pressure. The procedure was performed three times involving the addition of hexane (10 ml) followed by evaporation under reduced pressure to dryness to yield ethyl 2-chlorosulfonyl-1-cyclohexene-1 carboxylate. The total was combined with ethyl acetate (12 ml) and the resulting mixture was added to a mixture consisting of 3-fluoroaniline (0.48 g), triethylamine (0.60 ml) and ethyl acetate (6 ml). ice-ice and then stirred, ice-cooled for 30 minutes and then at room temperature for 25 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (50 ml) and 0.5 N HCl (50 ml) and water (50 ml × 2) and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. . The rest was purified by chromatography on silica gel (eluent: ethyl acetate / hexane = 1/3) and the first solution after passing through the column was distilled under reduced pressure and the residues were crystallized from diisopropyl ether to give 6- [N -3-fluorophenyl] sulfamoyl) -1-cyclohexene-1-ethyl (compound 11; 250 mg) as white powdered crystals. 1 H-NMR (DMSO-d 6) d: 1.16 (3H, t, J = 7.0 Hz), 1.60-1.80 (2H, m), 2.00-2.33 (4H, m), 3.98-4.15 (2H, m), 4.37 (1H, d, J = 4.8Hz), 6.87 (1H, dt, J = 8.4Hz, 2.2Hz), 7.00-7.17 (3H, m), 7.34 (1H, dt, J = 8.4Hz, 7.0Hz), 10.33 (1H, brs). Calculated values (%) for C 15 H 18 FNO 4 S: C-55.03; H-5.54; N, 4.28 Found (%): C, 55.09; H, 5.44; N-4.33. Example 11 Ethyl 2-sulfo-1-cyclohexene-1 carboxylate (0.72 g), obtained by the method a indicated in Reference Example 1, was dissolved in thionyl chloride (2.1 ml) and heated at reflux for 5 hours and then the reaction mixture was evaporated to dryness under reduced pressure. The procedure was performed three times involving the addition of hexane (10 ml) followed by evaporation under reduced pressure to dryness to yield 2-chlorosulfonyl-1-cyclohexene-1-ethyl carboxylate. The total was combined with ethyl acetate (10 ml) and the resulting mixture was added to a mixture consisting of 4-fluoroaniline (0.34 g), triethylamine (0.43 ml) and ethyl acetate (4 ml). , cooled with ice and then stirred, cooled with ice for 30 minutes and then at room temperature for 40 hours. The reaction mixture was diluted with ethyl acetate (30 ml) and washed with water (30 ml) and 0.5 N HCl (30 ml) and water (30 ml × 2) and dried over anhydrous magnesium sulfate and then dissolved the dish was distilled off. The rest was purified by chromatography on silica gel (eluent: ethyl acetate / hexane = 1/4) and the first solution after passing through the column was distilled off under reduced pressure and the residues were crystallized from diisopropyl ether to give 1,1-dioxide. 2- (4-fluorophenyl) -4,5,6,7-tetrahydro-1,2-benzisothiazol-3 (2H) -one (compound 68; 33 mg) in the form of white powdered crystals. The second solution, after passing through the columns, was distilled under reduced pressure and the obtained residue was crystallized from ethyl acetate-diisopropyl ether to give white powdery crystals. This compound was purified by column chromatography on an ODS column (eluent: methanol / water = 7/3), and the solution passed through the column was concentrated under reduced pressure to precipitate crystals which were then collected by filtration to give 6- [N- (4-fluorophenyl) sulfamoyl) -1-cyclohexene-1-ethyl carboxylate (compound 12; 36 mg) as colorless needle-shaped crystals. The mother liquors, obtained when the first solution was passed through the columns, were crystallized from ethyl acetate-diisopropyl ether mixture, concentrated under reduced pressure and then purified by column chromatography on ODS columns (eluent: methanol / water = 7/3) to give 2- [N- (4-fluorophenyl) sulfamoyl) -1-cyclohexene-1-ethyl carboxylate (compound 18; 25 mg) as colorless powdered crystals. Compound 12: 1H-NMR (DMSO-d6) d: 1.14 (3H, t, J = 7.2Hz), 1.55-1.77 (2H, m), 1.98-2, 44 (4H, m), 3.97-4.13 (2H, m), 4.28 (1H, d, J = 4.2Hz), 7.10-7.28 (5H, m), 10, 03 (1H, brs). Calculated values (%) for C 15 H 18 NO 4 S: C-55.03; H-5.54; N, 4.28 Found (%): C, 54.69; H, 5.43; N, 4.38 Compound 18: 1 H-NMR (DMSO-d 6) d: 1.20 (3H, t, J = 7.2Hz), 1.54 (4H, br), 2.25 (4H , br), 4.11 (2H, q, J = 7.2Hz), 7.12 (2H, s), 7.16 (2H, s), 10.11 (1H, brs). Calculated values (%) for C 15 H 18 NO 4 S: C-55.03; H-5.54; N, 4.28 Found (%): C, 55.07; H 5.35; N, 4.33 Compound 68: 1 H-NMR (DMSO-d 6) d: 1.75-1.88 (4H, m), 2.42-2.64 (4H, m), 7.40 -7.49 (4H, m). Calculated values (%) for C 13 H 12 FNO 3 S: C, 55.51; H, 4.30; N, 4.98 Found (%): C, 55.44; H, 4.24; N-4.94. Example 12 2-sulfo-1-cyclohexene-1-ethyl carboxylate (1.0 g), prepared by the method a indicated in Reference example 1, was dissolved in thionyl chloride (3.0 ml) and heated to a temperature of under reflux for 12 hours, and then the reaction mixture was evaporated under reduced pressure to dryness. The procedure was performed three times involving the addition of hexane (10 ml) followed by evaporation under reduced pressure to dryness to yield ethyl 2-chlorosulfonyl-1-cyclohexene-1 carboxylate. The total was combined with ethyl acetate (14 ml) and the resulting mixture was added to a mixture consisting of 2,6-difluoroaniline (0.56 g), triethylamine (0.60 ml) and ethyl acetate (6 ml), cooled with ice and then stirred, cooled with ice for 30 minutes and then at room temperature for 64 hours. The reaction mixture was diluted with ethyl acetate (80 ml) and washed with water (100 ml). The ethyl acetate layer was washed with 0.5 N HCl (100 ml × 2) and dilute brine (100 ml × 3) and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate / hexane = 1/3) and then crystallized from diisopropyl ether to give 6- [N- (2,6-difluorophenyl) sulfamoyl] -1- carboxylate. cyclohexene-1-ethyl (compound 13; 135 mg) as colorless powdered crystals. 1 H-NMR (DMSO-d 6) d: 1.00 (3H, t, J = 7.0 Hz), 1.59-1.88 (2H, m), 2.08-2.56 (4H, m), 3.97 (2H, dq, J = 7.0Hz, 1.4Hz), 4.39 (1H, d, J = 5.0Hz), 7.07-7.25 (3H, m), 7.34-7.50 (1H, m), 9.70 (1H, br s). Calculated values (%) for C 15 H 17 F 2 NO 4 S: C-52.17; H, 4.96; N, 4.06 Found (%): C, 51.76; H, 4.88; N-4.04. Example 13 2-sulfo-1-cyclohexene-1-ethyl carboxylate (1.0 g), prepared by the method a indicated in reference example 1, was dissolved in thionyl chloride (3.0 ml) and heated to a temperature of under reflux for 9 hours and then the reaction mixture was evaporated under reduced pressure to dryness. The procedure was performed three times involving the addition of hexane (10 ml) followed by evaporation under reduced pressure to dryness to yield ethyl 2-chlorosulfonyl-1-cyclohexene-1 carboxylate. The total was combined with ethyl acetate (14 ml) and the resulting mixture was added to a mixture consisting of 2,3-difluoroaniline (0.56 g), triethylamine (0.60 ml) and ethyl acetate (6 ml), cooled with ice and then stirred, cooled with ice for 30 minutes and then at room temperature for 15 hours. The reaction mixture was diluted with ethyl acetate (80 ml) and washed with water (100 ml). The ethyl acetate layer was washed with 1 N HCl (100 ml × 2) and dilute brine (100 ml × 3) and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by chromatography on silica gel (eluent: ethyl acetate / hexane = 1/4) and then crystallized from diisopropyl ether to give 6- [N- (2,3-difluorophenyl) sulfamoyl] -1- carboxylate. cyclohexene-1-ethyl (compound 14; 310 mg) as colorless powdered crystals. 1 H-NMR (DMSO-d 6) d: 1.10 (3H, t, J = 7.0 Hz), 1.58-1.83 (2H, m), 1.98-2.43 (4H, m), 4.02 (2H, q, J = 7.0Hz), 4.38 (1H, d, J = 4.4Hz), 7.13-7.36 (4H, m), 10.22 ( 1H, s). Calculated values (%) for C 15 H 17 F 2 NO 4 S: C-52.17; H, 4.96; N, 4.06 Found (%): C, 52.18; H, 4.88; N-4,11. Example 14 2-sulfo-1-cyclohexene-1-ethyl carboxylate (1.0 g), obtained by the method a indicated in reference example 1, was dissolved in thionyl chloride (3.0 ml) and heated to a temperature of refluxing for 24 hours and then the reaction mixture was evaporated under reduced pressure to dryness. The procedure was performed three times involving the addition of hexane (10 ml) followed by evaporation under reduced pressure to dryness to yield ethyl 2-chlorosulfonyl-1-cyclohexene-1 carboxylate. The total was combined with ethyl acetate (14 ml) and the resulting mixture was added to a mixture consisting of 2,5-difluoroaniline (0.56 g), triethylamine (0.60 ml) and ethyl acetate (6 ml), cooled with ice and then stirred, cooled with ice for 30 minutes and then at room temperature for 22 hours. The reaction mixture was diluted with ethyl acetate (80 ml) and washed with water (100 ml). The ethyl acetate layer was washed with 1 N HCl (100 ml × 2) and dilute brine (100 ml × 3) and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by chromatography on silica gel (eluent: ethyl acetate / hexane = 1/4) and then crystallized from diisopropyl ether to give 6- [N- (2,5-difluorophenyl) sulfamoyl] - carboxylate. 1-cyclohexene-1-ethyl (compound 15; 200 mg) in the form of colorless powdered crystals. 1 H-NMR (DMSO-d 6) d: 1.13 (3H, t, J = 7.0 Hz), 1.58-1.82 (2H, m), 2.05-2.43 (4H, m), 4.04 (2H, q, J = 7.0Hz), 4.38 (1H, d, J = 3.6Hz), 6.95-7.07 (1H, m), 7.13- 7.18 (1H, m), 7.25-7.39 (2H, m), 10.24 (1H, br s). Calculated values (%) for C 15 H 17 F 2 NO 4 S: C-52.17; H, 4.96; N, 4.06 Found (%): C, 52.23; H, 4.86; N-4,11. Example 15 Ethyl 2-sulfo-1-cyclohexene-1 carboxylate (1.0 g), prepared by the method a indicated in Reference Example 1, was dissolved in thionyl chloride (3.0 ml) and heated to a temperature of under reflux for 23 hours, and then the reaction mixture was evaporated to dryness under reduced pressure. The procedure was performed three times involving the addition of hexane (10 ml) followed by evaporation under reduced pressure to dryness to yield ethyl 2-chlorosulfonyl-1-cyclohexene-1 carboxylate. The total was combined with ethyl acetate (14 ml) and the resulting mixture was added to a mixture consisting of 3,4-difluoroaniline (0.56 g), triethylamine (0.60 ml) and ethyl acetate (6 ml), cooled with ice and then stirred, cooled with ice for 30 minutes and then at room temperature for 21 hours. The reaction mixture was diluted with ethyl acetate (80 ml) and washed with water (100 ml). The ethyl acetate layer was washed with 1 N HCl (100 ml × 2) and dilute brine (100 ml × 3) and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by chromatography on silica gel (eluent: ethyl acetate / hexane = 1/4) and then crystallized from diisopropyl ether to give 6- [N- (3,4-difluorophenyl) sulfamoyl] -1- carboxylate. cyclohexene-1-ethyl (compound 16; 170 mg) as colorless powdered crystals. 1 H-NMR (DMSO-d 6) d: 1.16 (3H, t, J = 7.0 Hz), 1.58-1.80 (2H, m), 1.98-2.42 (4H, m), 3.99-4.15 (2H, m), 4.34 (1H, d, J = 3.6Hz), 6.96-7.04 (1H, m), 7.13-7, 29 (2H, m), 7.41 (1H, dt, J = 10.6 Hz, 9.0 Hz), 10.29 (1H, brs). Calculated values (%) for C 15 H 17 F 2 NO 4 S: C-52.17; H, 4.96; N, 4.06 Found (%): C, 52.29; H, 4.78; N-4.04. Example 16 Ethyl 2-sulfo-1-cyclohexene-1 carboxylate (1.0 g), prepared by the method a indicated in Reference example 1, was dissolved in thionyl chloride (3.0 ml) and heated to a temperature of refluxing for 17 hours and then the reaction mixture was evaporated under reduced pressure to dryness. The procedure was performed three times involving the addition of hexane (10 ml) followed by evaporation under reduced pressure to dryness to yield ethyl 2-chlorosulfonyl-1-cyclohexene-1 carboxylate. The total was combined with ethyl acetate (14 ml) and the resulting mixture was added to a mixture consisting of 3,5-difluoroaniline (0.56 g), triethylamine (0.60 ml) and ethyl acetate (6 ml), cooled with ice and then stirred, cooled with ice for 30 minutes and then at room temperature for 21 hours. The reaction mixture was diluted with ethyl acetate (80 ml) and washed with water (100 ml). The ethyl acetate layer was washed with 1 N HCl (100 ml × 2) and dilute brine (100 ml × 3) and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by chromatography on silica gel (eluent: ethyl acetate / hexane = 1/3) and then crystallized from diisopropyl ether to give 6- [N- (3,5-difluorophenyl) sulfamoyl] -1- carboxylate. cyclohexene-1-ethyl (compound 17; 250 mg) as colorless powdered crystals. 1 H-NMR (DMSO-d 6) d: 1.18 (3H, t, J = 7.0 Hz), 1.58-1.82 (2H, m), 1.96-2.44 (4H, m), 3.99-4.16 (2H, m), 4.42 (1H, d, J = 4.8Hz), 6.83-6.95 (3H, m), 7.18 (1H, t, J = 4 Hz), 10.59 (1H, brs). Calculated values (%) for C 15 H 17 F 2 NO 4 S: C-52.17; H, 4.96; N, 4.06 Found (%): C, 52.22; H-5.01; N-4,12. Example 17 Ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (compound 3; 200 mg) obtained by method a indicated and in example 3 separated by method a high performance liquid chromatography HPLC (column Chiralpak AD; eluent: hexane / ethanol = 9/1) into two optical isomers to yield 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-ethyl 1-carboxylate ( Compound 19.62 mg) and 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1 d-ethyl carboxylate (compound 20.51 mg) each as a white powder. Compound 19 (40 mg) was crystallized from diisopropyl ether (2 ml) to give white powdered crystals (26 mg) of compound 19. 1 H-NMR (d 6 -DMSO) d: 1.07 (3H, t, J = 7.2 Hz), 1.58-1.82 (2H, m), 1.98-2.44 (4H, m), 4.01 (2H, q, J = 7.2Hz), 4.28 (1H, d, J = 4.6Hz), 7.04-7.15 (2H, m), 7.28- 7.54 (2H, m), 9.85 (1H, s). Calculated values (%) for C 15 H 17 F 2 NO 4 S: C-52.17; H, 4.96; N, 4.06 Found (%): C, 52.20; H, 4.85; N-4.20 [a] 20 D -105.7 ° (c = 0.5, in methanol) Compound 20 (35 mg) was crystallized from diisopropyl ether (2 ml) to give white powdered crystals (18 mg ) compound 20. 1 H-NMR (d 6 -DMSO) d: 1.07 (3H, t, J = 7.2 Hz), 1.58-1.82 (2H, m), 1.98-2.44 (4H, m), 4.01 (2H, q, J = 7.2Hz), 4.28 (1H, d, J = 4.6Hz), 7.05-7.15 (2H, m), 7.28- 7.55 (2H, m), 9.86 (1H, br s). Calculated values (%) for C 15 H 17 F 2 NO 4 S; C, 52.17; H, 4.96; N, 4.06 Found (%): C, 52.10; H, 4.83; N-4.21 [a] 20 D + 105.9 ° (0 = 0.5, in methanol). Example 18 2-sulfo-1-cyclohexene-1-ethyl carboxylate (2.0 g), obtained by the method and indicated In Reference Example 1, it was dissolved in thionyl chloride (6 ml) and refluxed for 15 hours, and then the reaction mixture was evaporated in vacuo to dryness. The procedure was performed three times involving the addition of hexane (10 ml) followed by evaporation under reduced pressure to dryness to yield ethyl 2-chlorosulfonyl-1-cyclohexene-1 carboxylate. The total was combined with ethyl acetate (20 ml) and the resulting mixture was added to a mixture consisting of ethyl anthranilate (1.42 g), triethylamine (1.20 ml) and ethyl acetate (12 ml). it was cooled with ice and then stirred, cooled with ice for 30 minutes and then at room temperature for 70 hours. The reaction mixture was diluted with ethyl acetate (80 ml) and washed with water (100 ml), 1 N HCl (100 ml x 2) and diluted brine (100 ml x 3) and dried over anhydrous magnesium sulfate and then the solvent was distilled off. The residue was purified by chromatography on silica gel (eluent: ethyl acetate / hexane = 1/4) and then crystallized from diisopropyl ether to yield 6- [N- (2-ethoxycarbonylphenyl) sulfamoyl] -1- carboxylate. cyclohexene-1-ethyl (compound 21; 0.44 g) as colorless crystals. 1 H-NMR (d 6 -DMSO) d: 1.12 (3H, t, J = 7.2 Hz), 1.35 (3H, t, J = 7.2 Hz), 1.62-1.84 ( 2H, m), 1.92-2.35 (4H, m), 3.85-4.10 (2H, m), 4.35 (2H, q, J = 7.2Hz), 4.50 ( 1H, d, J = 4.2Hz), 7.15-7.23 (2H, m), 7.60-7.72 (2H, m), 8.01 (1H, d, J = 8.0Hz ), 10.42 (1H, s). Calculated values (%) for C 18 H 23 NO 6 S: C, 56.68; H-6.08; N, 3.67 Found (%): C, 56.56; H, 6.05; N-3.68. Example 19 For a solution of ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (compound 3, 300 mg) obtained by method a indicated in example 3 in methanol (6 mL) Concentrated sulfuric acid (0.4 mL) was added, and the mixture was stirred at reflux for 8 days. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate (30 ml) and washed with water (30 ml). The ethyl acetate layer was washed with water (30 ml × 2) and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate / hexane = 1/5 - ethyl acetate / hexane = 1/2) and then crystallized from diisopropyl ether to yield 6- [N- (2 4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-ethyl (compound 22; 95 mg) as colorless powdered crystals. 1 H-NMR (d 6 -DMSO) d: 1.58-1.82 (2H, m), 1.98-2.42 (4H, m), 3.56 (3H, s), 4.30 (1H, d, J = 4.6 Hz), 7.05-7.15 (2H, m), 7.28-7.55 (2H, m), 9.85 (1H, s). Calculated values (%) for C 14 H 15 NO 4 S: C, 50.75; H-4.56; N, 4.23 Found (%): C, 50.79; H, 4.49; N-4.07. Example 20 For a solution of ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (compound 3, 300 mg) obtained by the method a indicated in example 3 in 1 -propanol (6 ml), concentrated sulfuric acid (0.3 ml) was added, and the mixture was stirred under reflux for 50 hours. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate (30 ml) and washed with water (30 ml). The ethyl acetate layer was washed with water (30 ml × 2) and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The remainder was chromatographed on silica gel (eluent: ethyl acetate / hexane = 1/5) and the desired fractions were concentrated under reduced pressure. The rest was purified by octadecyl silicon dioxide (ODS) column chromatography (eluent: methanol / water = 4/1) and then crystallized from diisopropyl ether to give 6- [N- (2,4-difluorophenyl) carboxylate ) sulfamoyl] -1-cyclohexene-1-propyl (compound 23, 60 mg) as colorless crystals. 1 H-NMR (d 6 -DMSO) d: 0.79 (3H, t, J = 7.4 Hz), 1.38-1.82 (4H, m), 2.02-2.45 (4H, m), 3.91 (2H, t, J = 6.4Hz), 4.27 (1H, d, J = 4.8Hz), 7.05-7.12 (2H, m), 7.28- 7.53 (2H, m), 9.86 (1H, s). Calculated values (%) for C 16 H 19 F 2 NO 4 S: C, 53.47; H, 5.33; N, 3.90 Found (%): C, 53.01; H 5.34; N-3.63. Example 21 For a solution of ethyl 6- [N- (4-chloro-2-fluoro-phenyl) sulfamoyl] -1-cyclohexene-1-carboxylate, the method a indicated in Example 1 (compound 1, 250 mg) in methanol (5 ml), concentrated sulfuric acid (0.2 ml) was added, and the mixture was stirred under reflux for 8 days hours. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate (30 ml) and washed with water (30 ml). The ethyl acetate layer was washed with water (30 ml × 2) and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel (eluent: ethyl acetate / hexane = 1/4) and the desired fractions were concentrated under reduced pressure. The residue was purified by column chromatography on an ODS column (eluent: methanol / water = 4/1) and then crystallized from diisopropyl ether to give 6- [N- (4-chloro-2-fluorophenyl) sulfamoyl carboxylate ] -1-cyclohexene-1-methyl (compound 24, 58 mg) as prismatic crystals. 1 H-NMR (d 6 -DMSO) d: 1.58-1.82 (2H, m), 1.98-2.44 (4H, m), 3.56 (3H, s), 4.34 (1H, br), 7.14 (1H, br), 7.25-7.50 (3H, m), 10.04 (1H, br s). Calculated values (%) for C 14 H 15 ClFM 4 S: C, 48.35; H, 4.35; N, 4.03 Found (%): C, 48.27; H, 4.43; N-4.08. Example 22 For a solution of ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate prepared by method a indicated in example 3 (compound 3, 200 mg) in 2-propanol (4 ml), concentrated sulfuric acid (0.2 ml) was added, and the mixture was stirred under reflux for 10 daily hours. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate (30 ml) and washed with water (30 ml). The ethyl acetate layer was washed with diluted brine (30 ml × 2) and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by chromatography on silica gel (eluent: ethyl acetate / hexane = 1/4) and then crystallized from diisopropyl ether to yield 6- [N- (2,4-difluorophenyl) sulfamoyl] -1- carboxylate. cyclohexene-1-isopropyl (compound 25, 20 mg) as white powdered crystals. 1 H-NMR (d 6 -DMSO) d: 1.04 (3H, d, J = 6.4 Hz), 1.09 (3H, d, J = 6.4 Hz), 1.58-1.82 ( 2H, m), 2.02-2.45 (4H, m), 4.25 (1H, d, J = 4.8Hz), 4.83 (1H, quintet. J = 6.4 Hz), 7.05-7.15 (2H, m), 7.30-7.54 (2H, m), 9.86 (1H, s). Calculated values (%) for C 16 H 19 F 2 NO 4 S: C, 53.47; H, 5.33; N, 3.90 Found (%): C, 53.67; H-5.09; N-3.77. Example 23 Ethyl 2-sulfo-1-cyclohexene-1 carboxylate (1.0 g), prepared by the method a indicated in Reference example 1, was dissolved in thionyl chloride (3 ml) and heated under reflux under with reflux for 9 hours and then the reaction mixture was evaporated to dryness under reduced pressure. The procedure was carried out three times involving the addition of hexane (10 ml) followed by evaporation under reduced pressure to dryness to give 2-chlorosulfonyl-1-cyclohexene-1-ethyl carboxylate. The total was combined with ethyl acetate (12 ml) and the resulting mixture was added to a mixture consisting of methyl anthranilate (0.65 g), triethylamine (0.60 ml) and ethyl acetate (6 ml), and cooled. with ice and then stirred, chilled with ice for 30 minutes and then at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (50 ml). The ethyl acetate layer was washed with 0.1 N HCl (50 ml × 2) and saturated brine (50 ml) and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by flash column chromatography (eluent: ethyl acetate / hexane = 1/5) and then crystallized from diisopropyl ether to give 6- [N- (2-methoxycarbonylphenyl) sulfamoyl] -1 carboxylate. -cyclohexene-1-ethyl (compound 26; 190 mg) as light yellow crystals in powder form. 1 H-NMR (d 6 -DMSO) d: 1.21 (3H, t, J = 7.0 Hz), 1.68-2.36 (6H, m), 3.90 (3H, s), 3 , 93-4.07 (2H, m), 4.50 (1H, d, J = 4.4Hz), 7.15-7.23 (2H, m), 7.61-7.69 (2H, m), 8.0 (1H, d, J = 8.8Hz), 10.39 (1H, s). Calculated values (%) for C 17 H 21 NO 6 S: C, 55.57; H, 5.76; N, 3.81 Found (%): C, 55.62; H, 5.76; N-3.78. Example 24 In a similar procedure to that indicated in example 23, ethyl 2-sulfo-1-cyclohexene-1 carboxylate (1.0 g), obtained by the method a indicated in reference example 1, was converted to carboxylate 2 -chlorosulfonyl-1-cyclohexene-1-ethyl which was then reacted with 2-fluoro-4-methylaniline (0.54 g) to give 6- [N- (2-fluoro-4-methylphenyl) sulfamoyl] - carboxylate Ethyl 1-cyclohexene-1 (compound 27; 223 mg) in the form of colorless powdered crystals. 1 H-NMR (d 6 -DMSO) d: 1.08 (3H, t, J = 7.0 Hz), 1.62-1.80 (2H, m), 2.00-2.43 (4H, m), 2.29 (3H, s), 4.01 (2H, q, J = 7.0Hz), 4.27 (1H, d, J = 5.0Hz), 6.97-7.11 ( 3H, m), 7.33 (1H, t, J = 8.4 Hz), 9.71 (1H, s). Calculated values (%) for C 16 H 20 FNO 4 S: C, 56.29; H, 5.90; N, 4.10 Found (%): C, 56.26; H, 5.80; N-4.03. Example 25 In a similar procedure to that indicated in example 23, ethyl 2-sulfo-1-cyclohexene-1 carboxylate (1.0 g), obtained by the method a indicated in reference example 1, was converted to carboxylate 2 -chlorosulfonyl-1-cyclohexene-1-ethyl, which was then reacted with o-chloroaniline (0.55 g) to give ethyl 6- [N- (2-chlorophenyl) sulfamoyl] -1-cyclohexene-1 carboxylate (comp. azek 28; 0.28 g) in the form of white crystals. 1 H-NMR (d 6 -DMSO) d: 1.05 (3H, t, J = 7.0 Hz), 1.55-1.84 (2H, m), 1.99-2.58 (4H, m), 4.00 (2H, q, J = 7.0Hz), 4.30 (1H, d, J = 5.2Hz), 7.11 (1H, br), 7.19-7.39 ( 2H, m), 7.48-7.56 (2H, m), 9.66 (1H, s). Calculated values (%) for C 15 H 18 ClNO 4 S: C, 52.40; H 5.28; N, 4.07 Found (%): C, 52.39; H 5.28; N-4.19. Example 26 In a similar procedure to that indicated in example 23, ethyl 2-sulfo-1-cyclohexene-1 carboxylate (1.0 g), obtained by the method a indicated in reference example 1, was converted to carboxylate 2 -chlorosulfonyl-1-cyclohexene-1-ethyl and reacted with 2-chloro-4-fluoroaniline (0.62 g) to give 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1 carboxylate -cyclohexene-1-ethyl (compound 29; 0.35 g) as white crystals. 1 H-NMR (d 6 -DMSO) d: 1.05 (3H, t, J = 7.0 Hz), 1.52-1.83 (2H, m), 1.98-2.46 (4H, m), 4.00 (2H, q, J = 7.0Hz), 4.29 (1H, d, J = 4.8Hz), 7.10 (1H, br), 7.20-7.30 ( 1H, m), 7.49-7.58 (2H, m), 9.80 (1H, s). Calculated values (%) for C 15 H 17 ClFNO 4 S: C, 49.79; H-4.74; N, 3.87 Found (%): C, 49.74; H, 4.76; N-3.98. Example 27 In a similar procedure to that indicated in example 23, ethyl 2-sulfo-1-cyclohexene-1 carboxylate (1.0 g), obtained by the method a indicated in reference example 1, was converted to carboxylate 2 -chlorosulfonyl-1-cyclohexene-1-ethyl, which was then reacted with p-chloroaniline (0.54 g) to give 6- [N- (4-chlorophenyl) sulfamoyl] -1-cyclohexene-1-ethyl carboxylate (comp. azek 30; 0.24 g) in the form of white crystals. 1 H-NMR (d 6 -DMSO) d: 1.15 (3H, t, J = 7.0 Hz), 1.51-1.78 (2H, m), 1.95-2.20 (4H, m), 3.96-4.13 (2H, m), 4.32 (1H, d, J = 4.0Hz), 7.13 (1H, t, J = 4.0Hz), 7.20- 7.24 (2H, m), 7.34-7.39 (2H, m), 10.17 (1H, s). Calculated values (%) for C 15 H 18 ClNO 4 S: C, 52.40; H 5.28; N, 4.07 Found (%): C, 52.33; H-5.11; N-3.87. Example 28 In a similar procedure to that indicated in example 23, ethyl 2-sulfo-1-cyclohexene-1 carboxylate (1.0 g), obtained by the method a indicated in reference example 1, was converted to carboxylate 2 -chlorosulfonyl-1-cyclohexene-1-ethyl which was then reacted with 2,3,4-trifluoroaniline (0.63 g) to give 6- [N- (2,3,4-trifluorophenyl) sulfamoyl] - carboxylate Ethyl 1-cyclohexene-1 (compound 31; 0.36 g) as white crystals. 1 H-NMR (d 6 -DMSO) d: 1.11 (3H, t, J = 7.0 Hz), 1.54-1.86 (2H, m), 1.95-2.48 (4H, m), 4.03 (2H, q, J = 7.0Hz), 4.34 (1H, d, J = 4.4Hz), 7.13 (1H, br), 7.29-7.35 ( 2H, m), 10.15 (1H, s). Calculated values (%) for C 15 H 16 F 3 NO 4 S: C, 49.58; H, 4.44; N, 3.85 Found (%): C, 49.51; H, 4.35; N-3.76PL 203 663 B1 40 Example 29 For a solution of ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate obtained by method a indicated in example 3 (compound 3) 200 mg) in iso-butyl alcohol (4 ml), concentrated sulfuric acid (0.2 ml) was added, and the mixture was stirred at 80 to 85 ° C for 7 days. After cooling, the reaction mixture was diluted with ethyl acetate (80 ml) and washed with water (50 ml). The ethyl acetate layers were washed with 5% aqueous sodium hydrogen carbonate (50 ml) and water (50 ml x 2), dried over anhydrous magnesium sulfate and then evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (eluent: ethyl acetate / hexane = 1/4) and then crystallized from diisopropyl ether to yield 6- [N- (2,4-difluorophenyl) sulfamoyl] -1- carboxylate. cyclohexene-1 isobutyl (compound 32; 35 mg) in the form of white crystals. 1 H-NMR (d 6 -DMSO) d: 0.80 (6H, d, J = 6.8 Hz), 1.58-1.84 (2H, m), 2.00-2.47 (4H, m), 3.35-3.45 (1H, m), 3.75 (2H, d, J = 6.8Hz), 4.27 (1H, d, J = 4.8Hz), 7.03- 7.13 (2H, m), 7.27-7.53 (2H, m), 9.35 (1H, s). Calculated values (%) for C 17 H 21 F 2 NO 4 S: C-54.68; H, 5.67; N, 3.75 Found (%): C, 54.64; H, 5.49; N-3.78. Example 30 For a solution of ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate obtained by method a indicated in example 3 (compound 3, 180 mg) in 1-butanol (5 ml), concentrated sulfuric acid (0.12 ml) was added and the mixture was stirred at 80 to 85 ° C for 7 days. After cooling the reaction mixture, it was diluted with ethyl acetate (60 ml) and washed with water (60 ml). The ethyl acetate layer was washed with water (60 ml × 5), dried over anhydrous magnesium sulfate and then evaporated under reduced pressure to dryness. The residue was purified by silica gel chromatography (eluent: ethyl acetate / hexane = 1/4) and then crystallized from diisopropyl ether to yield 6- [N- (2,4-difluorophenyl) sulfamoyl] -1- carboxylate. cyclohexene-1-butyl (compound 33, 52 mg) as white crystals. 1 H-NMR (d 6 -DMSO) d: 0.83 (3H, t, J = 7 Hz), 1.18-1.82 (6H, m), 2.00-2.42 (4H, m) , 3.95 (2H, br), 4.24 (1H, d, J = 4.4Hz), 7.09 (2H, br), 7.30-7.49 (2H, m), 9.86 (1H, brs). Calculated values (%) for C 17 H 21 F 2 NO 4 S: C-54.68; H, 5.67; N, 3.75 Found (%): C, 54.64; H, 5.48; N-4.05. Example 31 In a similar procedure to that indicated in example 23, ethyl 2-sulfo-1-cyclohexene-1 carboxylate (1.0 g), obtained by the method a indicated in reference example 1, was converted to carboxylate 2 -chlorosulfonyl-1-cyclohexene-1-ethyl which was then reacted with 4-bromo-2-fluoroaniline (0.81 g) to give 6- [N- (4-bromo-2-fluorophenyl) sulfamoyl] carboxylate Ethyl -1-cyclohexene-1 (compound 34; 0.23 g) as white crystals. 1 H-NMR (d 6 -DMSO) d: 1.10 (3H, t, J = 7.0 Hz), 1.54-1.83 (2H, m), 1.92-2.46 (4H, m), 4.02 (2H, q, J = 7.0Hz), 4.32 (1H, d, J = 4.4Hz), 7.12 (1H, t, J = 4.2Hz), 7, 35-7.48 (2H, m), 7.56-7.63 (1H, m), 10.04 (1H, s). Calculated values (%) for C 15 H 17 BrFNO 4 S: C, 44.35; H, 4.22; N, 3.45 Found (%): C, 44.40; H, 4.25; N-3.76. Example 32 In a similar procedure to that indicated in example 23, ethyl 2-sulfo-1-cyclohexene-1 carboxylate (1.0 g), obtained by the method a indicated in reference example 1, was converted to carboxylate 2 -chlorosulfonyl-1-cyclohexene-1-ethyl which was then reacted with 2,4-dichloroaniline (0.69 g) to give 6- [N- (2,4-dichlorophenyl) sulfamoyl] -1-cyclohexene carboxylate. 1 ethyl (compound 35; 0.24 g) as white crystals. 1 H-NMR (d 6 -DMSO) d: 1.07 (3H, t, J = 7.0 Hz), 1.54-1.82 (2H, m), 1.95-2.45 (4H, m), 4.01 (2H, q, J = 7.0Hz), 4.32 (1H, d, J = 4.8Hz), 7.12 (1H, br), 7.40-7.67 ( 3H, m), 9.81 (1H, br s). Calculated values (%) for C 15 H 17 Cl 2 NO 4 S: C, 47.63; H-4.53; N, 3.70 Found (%): C, 47.67; H-4.59; N-3.89. Example 33 2-acetaminophen (0.29 g) was dissolved in ethyl acetate (2.4 ml) and the resulting solution was mixed with triethylamine (0.46 ml), chilled with ice and then the solution was added dropwise. Ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate (0.42 g) obtained by the method a indicated in the reference example in ethyl acetate (4.8 ml). The reaction mixture was stirred under a stream of nitrogen at 0 ° C for 30 minutes and then at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate and washed successively with water (40 ml), hydrochloric acid (40 ml), water (40 ml x 2) and then with saturated brine (40 ml). The ethyl acetate layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate / hexane = 1: 4), the desired fractions were concentrated and the residue was crystallized from a mixture of ethyl acetate and hexane to give 6- [N- (2- acetoxyphenyl) sulfamoyl] -1-cyclohexene-1-ethyl (compound 36; 0.25 g) as white crystals. 1 H-NMR (d 6 -DMSO) d: 1.12 (3H, t, J = 7.0 Hz), 1.58-1.83 (2H, m), 1.90-2.40 (4H, m), 2.68 (3H, s), 3.88-4.06 (2H, m), 4.48 (1H, d, J = 4.4Hz), 7.17-7.26 (2H, m), 7.65-7.71 (2H, m), 8.09-8.13 (IH, m), 11.31 (IH, s). Calculated values (%) for C 17 H 21 NO 5 S: C, 58.10; H-6.02; N, 3.99 Found (%): C, 58.12; H, 5.93; N-4,10. Example 34 In a similar procedure to that indicated in example 23, ethyl 2-sulfo-1-cyclohexene-1 carboxylate (1.0 g), obtained by the method a indicated in reference example 1, was converted to carboxylate 2 -chlorosulfonyl-1-cyclohexene-1-ethyl, which was then reacted with m-chloroaniline (0.54 g) to yield ethyl 6- [N- (3-chlorophenyl) sulfamoyl] -1-cyclohexene-1 carboxylate (comp. azek 37; 0.15 g) in the form of white crystals. 1 H-NMR (d 6 -DMSO) d: 1.16 (3H, t, J = 7.0 Hz), 1.54-1.81 (2H, m), 1.94-2.38 (4H, m), 4.00-4.15 (2H, m), 4.36 (1H, d, J = 4.4Hz), 7.07 (1H, br), 7.11-7.37 (4H, m), 10.29 (IH, s). Calculated values (%) for C 15 H 18 CINO 4 S: C, 52.40; H 5.28; N, 4.07 Found (%): C, 52.44; H, 5.21; N-4.32. Example 35 In a similar manner to that shown in Example 33, ethyl 2-chlorosulfonyl-1-cyclohexene-1 carboxylate (0.42 g), obtained by the method a indicated in reference example 2, was subjected to from 2,3-dichloroaniline (0.35 g) to give ethyl 6- [N- (2,3-dichlorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (compound 38; 0.23 g) in form of white crystals. 1 H-NMR (d 6 -DMSO) d: 1.08 (3H, t, J = 7.0 Hz), 1.55-1.86 (2H, m), 1.97-2.46 (4H, m), 4.01 (2H, q, J = 7.0Hz), 4.36 (1H, d, J = 4.8Hz), 7.13 (1H, br), 7.32-7.56 ( 3H, m), 9.87 (1H, s). Calculated values (%) for C 15 H 17 Cl 2 NO 4 S: C, 47.63; H-4.53; N, 3.70 Found (%): C, 47.43; H, 4.33; N-4.02. Example 36 In a similar procedure to that indicated in example 23, ethyl 2-sulfo-1-cyclohexene-1 carboxylate (1.0 g), obtained by the method a indicated in reference example 1, was converted to carboxylate 2 -chlorosulfonyl-1-cyclohexene-1-ethyl which was then reacted with o-ethylaniline (0.52 g) to give 6- [N- (2-ethylphenyl) sulfamoyl] -1-cyclohexene-1-ethyl carboxylate (comp. azek 39; 0.20 g) in the form of white crystals. 1 H-NMR (d 6 -DMSO) d: 1.06 (3H, t, J = 7.0 Hz), 1.16 (3H, t, J = 7.6 Hz), 1.52-1.86 ( 2H, m), 1.99-2.50 (4H, m), 2.72 (2H, q, J = 7.6Hz), 4.01 (2H, q, J = 7.0Hz), 4, 39 (1H, d, J = 4.8Hz), 7.10 (1H, br), 7.16-7.38 (4H, m), 9.18 (1H, s). Calculated values (%) for C 17 H 23 NO 4 S: C, 60.51; H, 6.87; N, 4.15 Found (%): C, 60.15; H, 6.70; N-4.10. Example 37 In a similar manner to Example 33, ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate (0.42 g) was prepared in Reference Example 2, reacted with 4- (2H- 1,2,3-triazol-2-yl) aniline (0.35 g) to give 6- [N- [4- (2H-1,2,3-triazol-2-yl) phenyl) - carboxylate sulfamoyl] -1-cyclohexene-1-ethyl (compound 40; 0.48 g) as white crystals. 1 H-NMR (d 6 -DMSO) d: 1.15 (3H, t, J = 7.0 Hz), 1.55-1.80 (2H, m), 2.02-2.44 (4H, m), 4.00-4.15 (2H, m), 4.38 (1H, d, J = 4.4Hz), 7.15 (1H, br), 7.39 (2H, d, J = 9.2 Hz), 7.96 (2H, d, J = 9.2 Hz), 8.08 (2H, s), 10.29 (1H, s). Calculated values (%) for C 17 H 2 ON 4 O 4 S: C-54.24; H 5.36; N, 14.88 Found (%): C, 54.38; H, 5.10; N-15.01. Example 38 In a similar manner to that shown in Example 33, ethyl 2-chlorosulfonyl-1-cyclohexene-1 carboxylate (0.41 g), prepared by the method a indicated in Reference Example 2, was subjected to From 2,5-dichloroaniline (0.34 g) to give ethyl 6- [N- (2,5-dichlorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (compound 41; 0) , 21 g) as white crystals. 1 H-NMR (d 6 -DMSO) d: 1.10 (3H, t, J = 7.0 Hz), 1.57-1.85 (2H, m), 1.96-2.45 (4H, m), 4.04 (2H, q, J = 7.0Hz), 4.36 (1H, d, J = 4.4Hz), 7.15 (1H, br), 7.25-7.31 ( 1H, m), 7.51-7.59 (2H, m), 9.90 (1H, s). Calculated values (%) for C 15 H 17 Cl 2 NO 4 S: C, 47.63; H-4.53; N, 3.70 Found (%): C, 47.75; H, 4.66; N-3.80. Example 39 In a similar manner to that shown in Example 33, ethyl 2-chlorosulfonyl-1-cyclohexene-1 carboxylate (0.40 g), obtained by the method a indicated in reference example 2, was reacted with 2-trifluoromethoxyaniline (0.37 g) to give ethyl 6- [N- (2-trifluoromethoxyphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (compound 42; 316 mg) as colorless powdered crystals. 1 H-NMR (d 6 -DMSO) d: 1.10 (3H, t, J = 7.0 Hz), 1.54-1.80 (2H, m), 2.00-2.51 (4H, m), 4.04 (2H, q, J = 7.0Hz), 4.38 (1H, d, J = 5.2Hz), 7.13-7.40 (4H, m), 7.59- 7.64 (1H, m), 10.02 (1H, s). Calculated values (%) for C 16 H 18 F 3 NO 5 S: C, 48.85; H, 4.61; N, 3.56 Found (%): C, 48.92; H, 4.62; N-3.81 Example 40 In a similar manner to that shown in Example 33, ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate (0.40 g), prepared by the method a indicated in reference example 2, was reacted with 2 , 4,5-trifluoroaniline (0.31 g) to give ethyl 6- [N- (2,4,5-trifluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (compound 43; 0.30 g) in the form of white crystals. 1 H-NMR (d 6 -DMSO) d: 1.13 (3H, t, J = 7.0 Hz), 1.55-1.85 (2H, m), 1.96-2.48 (4H, m), 4.05 (2H, q, J = 7.0Hz), 4.35 (1H, d, J = 4.4Hz), 7.14 (1H, br), 7.47-7.71 ( 2H, m), 10.17 (1H, s). Calculated values (%) for C 15 H 16 F 3 NO 4 S: C, 49.58; H, 4.44; N, 3.85 Found (%): C, 49.83; H, 4.32; N-4.01. Example 41 In a similar manner to that shown in Example 33, ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate (0.41 g), obtained by the method a indicated in reference example 2, was reacted with 4 - (2H-tetrazol-2-yl) aniline (0.34 g) to give 6- [N- [4- (2H-tetrazol-2-yl) phenyl) sulfamoyl] -1-cyclohexene-1 carboxylate ethyl (compound 44; 0.45 g) as white crystals. 1 H-NMR (d 6 -DMSO) d: 1.15 (3H, t, J = 7.0 Hz), 1.57-1.85 (2H, m), 1.97-2.45 (4H, m), 3.98-4.14 (2H, m), 4.42 (1H, d, J = 4.4Hz), 7.17 (1H, br), 7.46 (2H, d, J = 9.2 Hz), 8.04 (2H, d, J = 9.2 Hz), 9.20 (1H, s), 10.50 (1H, s). Calculated values (%) for C 16 H 19 N 5 O 4 S: C-50.92; H-5.07; N, 18.56 Found (%): C, 51.05; H 5.24; N-18.50. Example 42 In a similar manner to that shown in Example 33, ethyl 2-chlorosulfonyl-1-cyclohexene-1 carboxylate (0.42 g), prepared by the method a indicated in Reference Example 2, was subjected to from 2-chloro-4-methylaniline (0.31 g) to give ethyl 6- [N- (2-chloro-4-methylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (compound 45; 0) 27 g) as white crystals. 1 H-NMR (d 6 -DMSO) d: 1.06 (3H, t, J = 7.0 Hz), 1.51-1.83 (2H, m), 1.99-2.46 (4H, m), 2.29 (3H, s), 4.00 (2H, q, J = 7.0Hz), 4.29 (1H, d, J = 5.4Hz), 7.08 (1H, br) , 7.12-7.16 (1H, m), 7.33-7.41 (2H, m), 9.53 (1H, s). Calculated values (%) for C 16 H 20 ClNO 4 S: C, 53.70; H, 5.63; N, 3.91 Found (%): C, 53.67; H, 5.61; N-3.97. Example 43 In a similar manner to that shown in Example 33, ethyl 2-chlorosulfonyl-1-cyclohexene-1 carboxylate (0.41 g), obtained by the method a indicated in reference example 2, was subjected to a from 4-fluoro-2-methylaniline (0.26 g) to give 6- [N- (4-fluoro-2-methylphenyl) sulfamoyl] -1-cyclohexene-1-ethyl carboxylate (compound 46; 0) , 36 g) as white crystals. 1 H-NMR (d 6 -DMSO) d: 1.06 (3H, t, J = 7.0 Hz), 1.56-1.84 (2H, m), 2.00-2.46 (4H, m), 2.31 (3H, s), 4.01 (2H, q, J = 7.0Hz), 4.30 (1H, d, J = 5.0Hz), 6.96-7.13 ( 3H, m), 7.32-7.39 (IH, m), 9.24 (IH, s). Calculated values (%) for C 16 H 20 FNO 4 S: C, 56.29; H, 5.90; N, 4.10 Found (%): C, 56.33; H, 5.90; N-3.93. Example 44 In a similar manner to that shown in Example 33, ethyl 2-chlorosulfonyl-1-cyclohexene-1 carboxylate (0.41 g), prepared by the method a indicated in Reference Example 2, was subjected to from 2,6-dichloroaniline (0.34 g) to give ethyl 6- [N- (2,6-dichlorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (compound 47; 0.05 g) in form of white crystals. 1 H-NMR (d 6 -DMSO) d: PL 203 663 B1 43 1.03 (3H, t, J = 7.0 Hz), 1.55-1.90 (2H, m), 2.03-2 , 64 (4H, m), 3.94-4.04 (2H, m), 4.65 (1H, d, J = 5.6Hz), 7.06 (1H, br), 7.32-7 , 40 (1H, m), 7.54-7.58 (2H, m), 9.77 (1H, s). Calculated values (%) for C 15 H 17 Cl 2 NO 4 S: C, 47.63; H-4.53; N, 3.70 Found (%): C, 47.76; H, 4.49; N-3.54. Example 45 In a similar manner to that shown in Example 33, ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate (0.40 g), obtained by the method a indicated in reference example 2, was reacted with 4 - (1H-tetrazol-1-yl) aniline (0.33 g) to give ethyl 6- [N- [4- (1H-tetrazol-1-yl) phenyl) sulfamoyl] -1-cyclohexene-1 carboxylate (compound 48; 0.45 g) as white crystals. 1 H-NMR (d 6 -DMSO) d: 1.17 (3H, t, J = 7.0 Hz), 1.56-1.83 (2H, m), 1.98-2.46 (4H, m), 3.99-4.16 (2H, m), 4.41 (1H, d, J = 4.2Hz), 7.17 (1H, br), 7.42 (2H, d, J = 9.0Hz), 7.85, (2H, d, J = 9.0Hz), 10.01 (1H, s), 10.45 (1H, s). Calculated values (%) for C 16 H 19 N 5 C 4 S: C, 50.92; H-5.07; N, 18.56 Found (%): C, 50.86; H, 5.12; N-18.47. Example 46 In a similar manner to Example 33, ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate (0.39 g), obtained in Reference Example 2, was reacted with 4- (1H -1,2,3-triazol-1-yl) aniline (0.36 g) to give 6- [N- [4- (1H-1,2,3-triazol-1-yl) phenyl) carboxylate sulfamoyl] -1-cyclohexene-1-ethyl (compound 49; 0.41 g) as white crystals. 1 H-NMR (d 6 -DMSO) d: 1.17 (3H, t, J = 7.0 Hz), 1.57-1.82 (2H, m), 1.98-2.41 (4H, m), 4.02-4.12 (2H, m), 4.40 (1H, d, J = 4.6Hz), 7.16 (1H, br), 7.40 (2H, d, J = 8.8Hz), 7.84 (2H, d, J = 8.8Hz), 7.93 (1H, s), 8.73 (1H, s), 10.34 (1H, s). Calculated values (%) for C 17 H 20 N 4 O 4 S: C-54.24; H 5.36; N, 14.88 Found (%): C, 54.35; H 5.37; N-14.96. Example 47 In a similar manner to that shown in Example 33, ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate (0.37 g), prepared by the method a indicated in reference example 2, was reacted with 2 -trifluoromethylaniline (0.31 g) to give ethyl 6- [N- (2-trifluoromethylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (compound 50; 0.17 g as a colorless oil. 1 H-NMR (d 6 -DMSO) d: 1.08 (3H, t, J = 7.0 Hz), 1.54-1.87 (2H, m), 1.99-2.42 (4H, m), 4.03 (2H, q, J = 7.0Hz), 4.49 (1H, d, J = 5.0Hz), 7.15 (1H, br), 7.44-7.52 ( 1H, m), 7.64-7.70 (3H, m), 9.53 (1H, s). MS (m / z); 378 (MH +) Example 48 In a similar manner to Example 33, ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate (0.41 g), prepared by the method a indicated in reference example 2, was reacted with methyl p-aminobenzoate (0.32 g) to give ethyl 6- [N- (4-methoxycarbonylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (compound 51; 0.46 g) as white crystal. 1 H-NMR (d 6 -DMSO) d: 1.14 (3H, t, J = 7.0 Hz), 1.56-1.85 (2H, m), 1.99-2.40 (4H, m), 3.83 (3H, s), 3.96-4.13 (2H, m), 4.42 (1H, d, J = 2.2Hz), 7.17 (1H, br), 7 , 31 (2H, d, J = 8.8 Hz), 7.90 (2H, d, J = 8.8 Hz), 10.54 (1H, s). Calculated values (%) for C 17 H 21 NO 6 S: C, 55.57; H, 5.76; N, 3.81 Found (%): C, 55.69; H, 5.61; N-3.97. Example 49 For a solution of sodium 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (80 mg) obtained by the method a indicated in reference example 12, in N, N -dimethylformamide (1 ml), benzyl bromide (50 mg) was added, cooled with ice, and the mixture was stirred at 0 ° C for 4 hours and then at room temperature for 17 hours. The reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (20 ml). The ethyl acetate layer was washed with water (20 ml × 2) and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The rest was purified by chromatography on silica gel (eluent: ethyl acetate / hexane = 1/4) and crystallized from diisopropyl ether to yield 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene carboxylate -1 benzyl (compound 52, 14 mg) in the form of white powdered crystals. 1 H-NMR (d 6 -DMSO) d: 1.55-1.83 (2H, m), 1.98-2.44 (4H, m), 4.30 (1H, d, J = 4, 2Hz), 5.00 (1H, d, J = 13Hz), 5.11 (1H, d, J = 13Hz), 6.93-7.04 (1H, m), 7.17 (1H, t, J = 4 Hz), 7.24-7.51 (7H, m), 9.88 (1H, s). Calculated values (%) for C 20 H 19 F 2 NO 4 S: C, 58.96; H, 4.70; N, 3.44PL 203 663 B1 44 Found (%): C, 58.67; H, 4.70; N-3.49. Example 50 In a similar manner to Example 33, ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate (0.4 g), prepared by the method a indicated in reference example 2, was reacted with 4 - [2,3-bis (t-butoxycarbonyl) guanidinomethyl] -aniline (0.71 g) to form 6- [N- [4- [2,3-bis (t-butoxycarbonyl) guanidinomethyl] phenyl carboxylate ] sulfamoyl] -1-cyclohexene-1-ethyl (compound 53; 492 mg) as a white powder. 1 H-NMR (d 6 -DMSO) d: 1.15 (3H, t, J = 6.8 Hz), 1.40 (9H, s), 1.48 (9H, m), 1.50-1 , 64 (2H, m), 2.13-2.32 (4H, m), 3.97-4.19 (2H, m), 4.32 (1H, d, J = 4.0Hz), 4 , 46 (2H, d, J = 5.4Hz), 7.11 (1H, t, J = 4.0Hz), 7.21 (2H, d, J = 9.2Hz), 7.26 (2H, d, J = 9.2 Hz), 8.60 (1H, t, J = 5.4 Hz), 10.01 (1H, s), 11.52 (1H, s). Calculated values (%) for C 27 H 40 N 4 O 8 S: C-55.84; H, 6.94; N, 9.65 Found (%): C, 55.52; H, 6.95; N-9.42. Example 51 In a similar manner to that indicated in Example 33, ethyl 2-chlorosulfonyl-1-cyclohexene-1 carboxylate (0.40 g), obtained by the method a indicated in Reference Example 2, was subjected to cation with methyl 3-chloro-4-aminobenzoate (0.39 g) to give ethyl 6- [N- (2-chloro-4-methoxycarbonylphenyl) sulfamoyl] -1-cyclohexene-1 carboxylate (compound 54: 0, 20 g) in the form of white crystals. 1 H-NMR (d 6 -DMSO) d: 1.10 (3H, t, J = 7.0 Hz), 1.56-1.85 (2H, m), 1.99-2.43 (4H, m), 3.86 (3H, s), 4.02 (2H, q, J = 7.0Hz), 4.44 (1H, d, J = 4.0Hz), 7.18 (1H, br) , 7.71 (1H, d, J = 8.4Hz), 7.88 (1H, dd, J = 8.4Hz, 1.8Hz), 7.97 (1H, J, J = 1.8Hz), 9.96 (IH, s). Calculated values (%) for C 17 H 20 CINO 6 S: C, 50.81; H-5.02; N, 3.49 Found (%): C, 50.79; H, 4.98; N-3.45. Example 52 In a similar manner to Example 33, ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate (0.41 g), prepared by the method a indicated in reference example 2, was reacted with 4 -amino-3-chlorobenzonitrile (0.32 g) to give ethyl 6- [N- (2-chloro-4-cyanophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (compound 55; 0.16 g) in form of white crystals. 1 H-NMR (d 6 -DMSO) d: 1.12 (3H, t, J = 7.0 Hz), 1.56-1.84 (2H, m), 1.95-2.42 (4H, m), 4.03 (2H, q, J = 7.0Hz), 4.46 (1H, d, J = 4.8Hz), 7.20 (1H, br), 7.70-7.84 ( 2H, m), 8.07 (1H, br), 10.09 (1H, s). Calculated values (%) for C 16 H 17 ClN 2 O 4 S: C-52.10; H, 4.65; N, 7.60 Found (%): C, 52.15; H, 4.62; N-7.46. Example 53 For a solution of sodium 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (100 mg), obtained by the method a indicated in reference example 12, in N, 2-Bromoethanol (81 mg) was added to N-dimethylformamide (2 ml), cooled with ice, and the mixture was stirred at room temperature for 72 hours. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (30 ml). The ethyl acetate layer was washed with 5% aqueous sodium hydrogen carbonate solution (30 ml) and saturated brine (30 ml) and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by chromatography on silica gel (eluent: ethyl acetate / hexane = 1/1) and crystallized from diisopropyl ether to yield 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene carboxylate. 1 2-Hydroxyethyl (compound 56, 35 mg) as white powdered crystals. 1 H-NMR (d 6 -DMSO) d: 1.58-1.81 (2H, m), 2.00-2.42 (4H, m), 3.51 (2H, br), 4.00 (2H, t, J = 5.0Hz), 4.34 (1H, d, J = 4.4Hz), 4.77 (1H, br), 7.02-7.20 (2H, m), 7 , 26-7.37 (1H, m), 7.44-7.56 (1H, m), 9.82 (1H, br). Calculated values (%) for C 15 H 17 F 2 NO 5 S: C, 49.86; H-4.74; N, 3.88 Found (%): C, 49.65; H, 4.79; N-3.94. Example 54 In a similar manner to that indicated in Example 33, ethyl 2-chlorosulfonyl-1-cyclohexene-1 carboxylate (0.40 g), obtained by the method a indicated in Reference Example 2, was subjected to from 2-chloro-4- (1H-1,2,4-triazol-1-yl) aniline (0.37 g) to give 6- [N- [2-fluoro-4- - (1H- 1,2,4-triazol-1-yl) phenyl) sulfamoyl] -1-cyclohexene-1-ethyl (compound 57; 0.33 g) as white crystals. 1 H-NMR (d 6 -DMSO) d: 1.08 (3H, t, J = 7.0Hz), 1.50-1.69 (2H, m), 1.86-2 , 44 (4H, m), 4.00 (2H, q, J = 7.0Hz), 4.32 (1H, d, J = 4.4Hz), 7.10 (1H, br), 7.38 -7.47 (1H, m), 7.60 (1H, dd, J = 9.2Hz, 3.0Hz), 7.70 (1H, dd, J = 9.2Hz, 5.4Hz), 8. 30 (IH, s), 8.99 (IH, s), 9.64 (IH, s). Calculated values (%) for C 17 H 19 FN 4 O 4 S: C-51.77; H, 4.86; N, 14.20 Found (%): C, 51.51; H-5.01; N-14.06. Example 55 A solution of 2-chlorosulfonyl-1-cyclopentene-1-ethyl carboxylate (0.14 g), prepared by the method a indicated in reference example 3, in ethyl acetate (2 ml) was added to a mixture of 2.4 -difluoroaniline (0.1 g), triethylamine (0.17 ml) and ethyl acetate (2 ml) were cooled with ice and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate (30 ml) and washed with water (30 ml). The ethyl acetate layer was washed with 0.5 N HCl (30 ml × 2) and saturated brine (30 ml) and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The rest was subjected to flash column chromatography on silica gel (eluent: ethyl acetate / hexane = 1/5) and after the first solution had been distilled off the solvent in the first solution, 2- [N- (2,4-difluorophenyl) sulfamoyl carboxylate was obtained ] -1-cyclopentene-1-ethyl (compound 66, 16.2 mg) as a brown oil. After distilling off the solvent in the second solution after passing through the columns, e was crystallized from diisopropyl ether to give 5- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclopentene-1-ethyl carboxylate (compound 58, 22.8 mg ) in the form of colorless powdered crystals. Compound 58: 1 H-NMR (d 6 -DMSO) d: 1.14 (3H, t, J = 7.0 Hz), 2.26-2.74 (4H, m), 4.06 (2H, q, J = 7.0Hz), 4.50 (1H, d, J = 8.0Hz), 7.02-7.13 (2H, m), 7.24-7.52 (2H, m), 9.79 (1H, s). Calculated values (%) for C 14 H 15 F 2 NO 4 S: C-50.75; H-4.56; N, 4.23 Found (%): C, 50.64; H-4.51; N, 4.15 Compound 66: 1 H-NMR (CDCl 3) d: 1.34 (3H, t, J = 7.0Hz), 1.93 (2H, quintet, J = 7.6Hz), 2 , 69-2.88 (4H, m), 4.32 (2H, q, J = 7.0Hz), 6.79-6.93 (2H, m), 7.50-7.62 (1H, m), 7.96 (1H, s). Example 56 For a solution of sodium 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (112 mg) prepared by the method a indicated in reference example 12, in N, N-dimethylformamide (2 ml ), t-butyl bromoacetate (98 mg) was added, cooled with ice and the mixture was stirred at room temperature for 43 hours. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (30 ml). The ethyl acetate layer was washed with water (30 ml) and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by chromatography on silica gel (eluent: ethyl acetate / - hexane = 1/3) to give the carbonyloxyacetate [6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexen-1-yl ] t-butyl (compound 59, 118 mg) as white powdered crystals. 1 H-NMR (d 6 -DMSO) d: 1.40 (9H, s), 1.59-1.85 (2H, m), 2.01-2.46 (4H, m), 4.30 (1H, d, J = 5.0Hz), 4.50 (2H, s), 7.04-7.14 (1H, m), 7.21-7.54 (3H, m), 9.84 (1H, s). Example 57 To a solution of [6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexen-1-yl] t-butyl carbonyloxyacetate (compound 59, 80 mg) obtained by the method a indicated in example 56, in ethyl acetate (4 ml), a 4N solution of hydrogen chloride in ethyl acetate (5 ml) was added, cooled with ice, and the mixture was stirred at room temperature for 70 hours. The reaction mixture was evaporated under reduced pressure to dryness and the residues were purified by column chromatography on an ODS column (eluent: methanol / water = 3/2) to give acid [6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexen-1-yl] carbonyloxoacetic (compound 60, 25 mg) as white powdered crystals. 1 H-NMR (d 6 -DMSO) d: 1.60-1.82 (2H, m), 1.98-2.42 (4H, m), 4.32 (1H, d, J = 4, 4Hz), 4.52 (2H, s), 7.03-7.13 (1H, m), 7.21-7.54 (3H, m), 10.02 (1H, br), 13.0 (1H, br). SIMS: 375 (M +). Example 58 A solution of 2-chlorosulfonyl-1-cycloheptene-1-ethyl carboxylate (0.56 g), obtained by method a as shown in reference example 4, in ethyl acetate (3.5 ml) was added to a mixture of 2,4- di-fluoroaniline (0.35 g), triethylamine (0.42 ml) and ethyl acetate (2 ml), was cooled with ice, and the mixture was stirred at room temperature for 7 hours. The reaction mixture was diluted with ethyl acetate (30 ml) and washed with water (30 ml). The ethyl acetate layer was washed with 0.5 N HCl (30 ml × 2) and saturated brine (30 ml) and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The rest was subjected to flash column chromatography on silica gel (eluent: ethyl acetate / hexane = 1/8) and column chromatography on an ODS column (eluent: acetonitrile / water = 6/4) and then crystallized from hexane to give ethyl 7- [N- (2,4-difluorophenyl) sulfamoyl] -1-cycloheptene-1-ethyl carboxylate (compound 61; 25.7 mg) as colorless powdered crystals. 1 H-NMR (d 6 -DMSO) d: 1.12 (3H, t, J = 7.0 Hz), 1.60-1.90 (3H, m), 2.02-2.73 (5H, m), 4.03 (2H, q, J = 7.0Hz), 4.74 (1H, t, J = 4.0Hz), 7.07 (1H, t, J = 9.0Hz), 7, 26-7.35 (1H, m), 7.42-7.54 (2H, m), 9.84 (1H, s). Calculated values (%) for C 16 H 19 F 2 NO 4 S: C, 53.47; H, 5.33; N, 3.90 Found (%): C, 53.52; H-5.09; N-3.93. Example 59 In a similar manner to that shown in Example 33, ethyl 2-chlorosulfonyl-1-cyclohexene-1 carboxylate (0.30 g), obtained by the method a indicated in reference example 2, was subjected to a reaction cation with N- (4-amino-3-chlorobenzoyl) t-butyl glycinate (0.41 g) to give 6- [N- [2-chloro-4- (Nt-butoxycarbonylmethylcarbamoyl) phenyl] sulfamoyl] -1 carboxylate -cyclohexene-1-ethyl (compound 62; 0.18 g) as white crystals. 1 H-NMR (d 6 -DMSO) d: 1.10 (3H, t, J = 7.0 Hz), 1.42 (9H, s), 1.55-1.86 (2H, m), 1 , 98-2.46 (4H, m). 3.90 (2H, d, J = 5.8Hz), 4.03 (2H, q, J = 7.0Hz), 4.41 (1H, d, J = 4.2Hz), 7.16 (1H , br), 7.65 (1H, d, J = 8.4Hz), 7.83 (1H, dd, J = 8.4Hz, 1.8Hz), 7.98 (1H, d, J = 1, 8 Hz), 8.95 (1H, br), 9.89 (1H, s). Calculated values (%) for C 22 H 29 ClN 2 O 7 S: C, 49.58; H, 4.44; N, 3.85 Found (%): C, 49.51; H, 4.35; N-3.76. Example 60 Ethyl 6- [N- [2-chloro-4- (Nt-butoxycarbonylmethylcarbamoyl) phenyl] sulfamoyl] -1-cyclohexene-1-carboxylate (23 mg) was dissolved in ethyl acetate (0.10). 5 ml) and then mixed with 4 N hydrogen chloride ethyl acetate solution (1.8 ml) and the mixture was stirred at room temperature for 51 hours. The reaction mixture was diluted with ethyl acetate and then washed twice with saturated brine. The ethyl acetate layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 11: 14) to give 6- [N- [2-chloro-4- (N-ethoxycarbonylmethylcarbamoyl) phenyl] sulfamoyl] - carboxylate. Ethyl 1-cyclohexene-1 (compound 63; 18 mg) as a colorless oil. 1 H-NMR (d 6 -DMSO) d: 1.10 (3H, t, J = 7.0Hz), 1.21 (3H, t, J = 7.0Hz), 1.57-1.84 ( 2H, m), 1.91-2.38 (4H, m), 3.98-4.08 (4H, m), 4.12 (2H, q, J = 7.0Hz), 4.41 ( 1H, d, J = 4.4Hz), 7.16 (1H, br), 7.66 (1H, d, J = 8.5Hz), 7.83 (1H, dd, J = 8.5Hz, 1 , 8 Hz), 7.99 (1H, d, J = 1.8 Hz), 9.04 (1H, br), 9.89 (1H, s). Example 61 In a similar procedure to that of Example 55, ethyl 2-chlorosulfonyl-1-cyclopentene-1 carboxylate (0.39 g), obtained from the method indicated in Reference Example 3, was reacted with 2-chloro 4-fluoroaniline (0.31 g) to give 5- [N- (2-chloro-4-fluoro-phenyl) sulfamoyl] -1-cyclopentene-1-ethyl carboxylate (compound 64, 134 mg) as light yellow salt solid powdered crystals. 1 H-NMR (d 6 -DMSO) d: 1.15 (3H, t, J = 7.0 Hz), 2.22-2.74 (4H, m), 4.07 (2H, q, J = 7.0Hz), 4.50 (1H, d, J = 8.0Hz), 7.10 (1H, s), 7.18-7.28 (1H, m), 7.47-7.56 ( 2H, m), 9.70 (1H, s). Calculated values (%) for C 14 H 15 CIFNO 4 S: C, 48.35; H, 4.35; N, 4.03 Found (%): C, 48.42; H-4.07; N-4.04. Example 62 In a similar manner to that shown in Example 33, ethyl 2-chlorosulfonyl-1-cyclohexene-1 carboxylate (0.41 g), prepared by the method a indicated in Reference Example 2, was subjected to from 4- (2,2,3,3,3-pentafluoropropoxy) aniline (0.87 g) to give 2- [4- (2,2,3,3,3-pentafluoropropoxy) 1,1-dioxide ) phenyl] -4,5,6,7-tetrahydro-1,2-benzisothiazol-3 (2H) -one (compound 69; 0.09 g) as white crystals. 1 H-NMR (d 6 -DMSO) d: 1.69-1.91 (4H, m), 2.38-2.54 (4H, m), 4.92 (2H, t, J = 7, 4Hz), 7.26 (2H, d, J = 7.2Hz), 7.38 (2H, d, J = 7.2Hz). Calculated values (%) for C 16 H 14 F 5 NO 4 S: C, 46.72; H-3.43; N, 3.41 Found (%): C, 46.79; H, 3.38; N-3.29. Example 63 In a similar manner to that shown in example 58, ethyl 2-chlorosulfonyl-1-cycloheptene-1 carboxylate (0.38 g), obtained by the method indicated in reference example 4, was reacted from 2-chloro-4-fluoroaniline (0.27 g) to give 7- [N- (2-chloro-4-fluoro-phenyl) sulfamoyl] -1-cycloheptene-1-ethyl carboxylate (comp. azek 65, 19 mg) in the form of light yellow powdered crystals. 1 H-NMR (d 6 -DMSO) d: 1.23 (3H, t, J = 7.0 Hz), 1.19-1.38 (1H, m), 1.67-1.81 (3H, m), 2.02-2.15 (1H, m), 2.15-2.76 (3H, m), 4.05 (2H, q, J = 7.0Hz), 4.80 (1H, t, J = 4.6 Hz), 7.17-7.27 (1H, m), 7.44-7.59 (3H, m), 9.59 (1H, s). Calculated values (%) for C 16 H 19 CIFNO 4 S: C, 51.13; H, 5.10; N, 3.73 Found (%): C, 51.16; H, 5.19; N-3.89 Example 64 To a solution of N-methylmorpholine (41 mg) in N, N-dimethylformamide (1.5 ml), a solution of 6- [N- (2,4-difluorophenyl) sulfamoyl] -1- was added. cyclohexene-1-carboxylic acid (64 mg) obtained by the method a indicated in reference example 12, in N, N-dimethylformamide (1 ml), cooled with ice. To this mixture was added a solution of 1-hydroxybenzotriazole (41 mg) in N, N-dimethylformamide (0.5 ml) and dicyclohexylcarbodiimide (52 mg), and the mixture was stirred, chilled with ice for 1 hour and then at room temperature for 16 hours. hours. The reaction mixture was combined with ethyl acetate (20 ml) and the insoluble matter was filtered off. The filtrate was washed successively with 10% aqueous phosphoric acid (20 ml), water (20 ml), 5% aqueous sodium hydrogen carbonate (20 ml), water (20 ml) and then saturated brine ( 20 ml) and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The rest was combined with ethyl acetate (3 ml) and the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (eluent: ethyl acetate / hexane = 1/2) and crystallized from diisopropyl ether to give 2- 1,1-dioxide (2,4- difluorophenyl) -5,6,7,7a-tetrahydro-1,2-benzisothiazol-3 (2H) -one (compound 70, 25 mg) as white powdered crystals. 1 H-NMR (d 6 -DMSO) d: 1.59-1.82 (2H, m), 1.98-2.06 (1H, m), 2.37-2.46 (3H, m) , 4.84-4.91 (1H, m), 7.17-7.37 (2H, m), 7.49-7.65 (2H, m). SIMS: 300 (MH +). Example 65 In a similar manner to that indicated in example 33, ethyl 2-chlorosulfonyl-1-cyclohexene-1 carboxylate (11.8 g), obtained by the method a indicated in reference example 2, was subjected to by reaction with 2-chloro-4-fluoroaniline (8.84 g) to form 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-ethyl carboxylate (compound 29, 11.3 g) in the form of white crystals. This substance was identical in physicochemical terms to the compound 29 obtained by the method and indicated in example 26. Example 66 Ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (compound 29, 2.01 g) obtained by the method a indicated in example 65 was separated by the high-performance method HPLC liquid chromatography (column Chiralpak AD; eluent: hexane / ethanol = 9/1) for two optical isomers of 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate, respectively Ethyl ethyl (compound 71, 979 mg) and 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1 d-ethyl carboxylate (compound 72, 959 mg) as an oil. Compound 71 (833 mg) was crystallized from a mixture of diisopropyl ether and hexane to give colorless prismatic crystals (681 mg) of compound 71. 1 H-NMR (d 6 -DMSO) d: 1.05 (3H, t, J = 7.0 Hz), 1.55-1.84 (2H, m), 1.96-2.43 (4H, m), 4.00 (2H, q, J = 7.0Hz), 4.29 (1H, d, J = 5.0Hz), 7.10 (1H, br), 7.20-7.30 ( 1H, m), 7.50-7.58 (2H, m), 9.73 (1H, s). Calculated values (%) for C 15 H 17 ClFNO 4 S: C, 49.79; H-4.74; N, 3.87 Found (%): C, 49.55; H, 4.46; N-4.08 [a] 20 D -111.0 ° (c = 1.0, in methanol) Compound 72 (817 mg) was crystallized from a mixture of diisopropyl ether and hexane to give colorless prismatic crystals (634 mg) azku 72. 1 H-NMR (d 6 -DMSO) d: 1.05 (3H, t, J = 7.0 Hz), 1.56-1.83 (2H, m), 2.01-2.43 (4H, m), 4.00 (2H, q, J = 7.0Hz), 4.30 (1H, d, J = 5.0Hz), 7.10 (1H, br), 7.20-7.30 ( 1H, m), 7.50-7.58 (2H, m), 9.74 (1H, s). Calculated values (%) for C 15 H 17 ClFNO 4 S: C, 49.79; H-4.74; N, 3.87 Found (%): C, 49.67; H, 4.72; N-3.85 [a] 20 D + 111.0 ° (0 = 1.0, in methanol). Example 67 In a similar manner to example 33, ethyl 2-chlorosulfonyl-1-cyclohexene-1 carboxylate (0.43 g), prepared by the method a indicated in Reference Example 2, was reacted with 2-bromo-4-fluoroaniline (0.42 g) to give 6- [N- ( 2-bromo-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-ethyl (compound 73; 0.36 g) as white crystals. 1 H-NMR (d 6 -DMSO) d: 1.05 (3H, t, J = 7.0 Hz), 1.55-1.86 (2H, m), 1.99-2.45 (4H, m), 4.00 (2H, q, J = 7.0Hz), 4.33 (1H, d, J = 5.2Hz), 7.09 (1H, br), 7.24-7.34 ( 1H, m), 7.50-7.68 (2H, m), 9.64 (1H, s). Calculated values (%) for C 15 H 17 BrFNO 4 S: C, 44.35; H, 4.22; N, 3.45 Found (%): C, 44.27; H-4.16; N-3.73. Example 68 In a similar manner to that shown in Example 33, ethyl 2-chlorosulfonyl-1-cyclohexene-1 carboxylate (0.43 g), prepared by the method a indicated in Reference Example 2, was subjected to from 4-bromo-2-chloroaniline (0.45 g) to give ethyl 6- [N- (4-bromo-2-chlorophenyl) sulfamoyl] -1-cyclohexene-1 carboxylate (compound 74; 0) 23 g) as white crystals. 1 H-NMR (d 6 -DMSO) d: 1.08 (3H, t, J = 7.2 Hz), 1.45-1.83 (2H, m), 1.96-2.42 (4H, m), 4.01 (2H, q, J = 7.2Hz), 4.32 (1H, d, J = 5.2Hz), 7.12 (1H, br), 7.45-7.57 ( 2H, m), 7.76-7.78 (IH, m), 9.80 (IH, s). Calculated values (%) for C 15 H 17 BrClNO 4 S: C, 42.62; H-4.05; N, 3.31 Found (%): C, 42.49; H, 3.99; N-3.60. Example 69 2-Chlorosulfonyl-5-phenyl-1-cyclohexene-1-ethyl carboxylate (0.5 g), prepared by the method a shown in reference example 14, was added to the mixture of 2,4-difluoroaniline (0.26 g), triethylamine (0.42 ml) and ethyl acetate (3 ml), cooled with ice, and the mixture was stirred at room temperature for 7 hours. The reaction mixture was diluted with ethyl acetate (30 ml) and washed with water (30 ml). The ethyl acetate layer was washed with 0.5 N HCl (30 ml) and saturated brine (30 ml) and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The rest was subjected to flash column chromatography on silica gel (eluent: ethyl acetate / hexane = 1/10) and ODS flash column chromatography (eluent: methanol / water / acetic acid = 7/3 / 0.02) to give more polar diastereoisomer (compound 75, 56 mg, colorless crystals in powder form) and less polar diastereoisomer (compound 76.84 mg, colorless crystals in powder form) 6- [N- (2,4- difluorophenyl) sulfamoyl] -3-phenyl-1-cyclohexene-1-ethyl. More polar diastereoisomer (compound 75): 1 H-NMR (d 6 -DMSO) d: 1.08 (3H, t, J = 7.2 Hz), 1.90-2.57 (4H, m), 3 , 54-3.70 (1H, m), 4.04 (2H, q, J = 7.2Hz), 4.36 (1H, brs), 6.96-7.59 (9H, m), 9 . 98 (IH, s). Calculated values (%) for C 21 H 21 F 2 NO 4 S: C, 59.85; H-5.02; N, 3.32 Found (%): C, 59.86; H-5.03; N-3.21 Less polar diastereoisomer (compound 76): 1H-NMR (CDCl 3) d: 1.09 (3H, t, J = 7.4Hz), 1.55-1.61 (1H, m ), 1.81-1.99 (1H, m), 2.28-2.34 (1H, m), 2.49-2.59 (1H, m), 3.72-3.84 (1H , m), 4.05 (2H, q, J = 7.4Hz), 4.43 (1H, d, J = 5.0Hz), 7.03-7.57 (9H, m), 9.94 (1H, s). Calculated values (%) for C 21 H 21 F 2 NO 4 S: C, 59.85; H-5.02; N, 3.32 Found (%): C, 59.96; H, 5.17; N-3.17. Example 70 In a similar manner to that indicated in Example 69, ethyl 2-chlorosulfonyl-5-phenyl-1-cyclohexene-1-carboxylate (0.5 g), prepared by the method a indicated in example reference 14, was subjected to reaction with 2-chloro-4-fluoroaniline (0.29 g) to give a more polar diastereoisomer (compound 77, 89 mg, colorless powder crystals) and a less polar diastereoisomer (compound 78, 51 mg, colorless crystal ly in powder form), ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] - 3-phenyl-1-cyclohexene-1-carboxylate. More polar diastereoisomer (compound 77): 1H-NMR (d6-DMSO) d: 1.06 (3H, t, J = 7.0Hz), 1.88-2.26 (3H, m), 2 , 49-2.63 (1H, m), 3.58-3.67 (1H, m), 4.04 (2H, q, J = 7.0Hz), 4.0 (1H, d, J = 3.6Hz), 6.97 (1H, d, J = 2.6Hz), 7.22-7.41 (6H, m), 7.51-7.63 (2H, m), 9.85 ( 1H, s). Calculated values (%) for C 21 H 21 CIFNO 4 S: C-57.60; H, 4.83; N, 3.20 Found (%): C, 57.60; H, 4.87; N, 3.06 Less polar diastereoisomer (compound 78): 1H-NMR (CDCl3) d: 1.08 (3H, t, J = 7.2Hz), 1.54-1.63 (1H, m ), 1.81-1.98 (1H, m), 2.30-2.65 (2H, m), 3.77-3.79 (1H, m), 4.05 (2H, q, J = 7.2 Hz), 4.44 (1H, d, J = 4.8 Hz), 7.05-7.61 (9H, m), 9.83 (1H, s). Calculated values (%) for C 21 H 21 CIFNO 4 S: C-57.60; H, 4.83; N, 3.20 Found (%): C, 57.57; H, 4.86; N-3.07. Example 71 2,4-difluoroaniline (0.39 g) was dissolved in ethyl acetate (5 ml) and the resulting solution was mixed with triethylamine (0.65 ml), chilled with ice and then added dropwise. a solution of ethyl 5-t-butyl-2-chlorosulfonyl-1-cyclohexene-1-carboxylate (0.72 g) obtained by method a indicated in reference example 16, in ethyl acetate (9 ml). The reaction mixture was stirred under nitrogen flow at 0 ° C for 30 minutes, then at room temperature for 46 hours. The reaction mixture was diluted with ethyl acetate and washed successively with water (80 mL), 0.5 N HCl (80 mL), aq (80 mL x 2), and saturated brine (80 mL). The ethyl acetate layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The remainder was subjected to column chromatography over silica gel (eluent: ethyl acetate / hexane = 1/7 → 1/6) and the desired fractions were concentrated under reduced pressure. The remainder was subjected to the reverse phase pressure mean ODS (eluent: methanol / water = 6/4) and then high pressure liquid chromatography (YMC-Pack, ODS, eluent: acetonitrile / water = 55/45 60/40 ) to separate the more polar and less polar compounds. Each desired fraction was concentrated under reduced pressure and the residue was extracted with ethyl acetate and then washed with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and the residues were crystallized from a mixture of ethyl acetate and hexane to give a more polar diastereoisomer (compound 79; 0.08 g) and a less polar diastereoisomer (compound 80; 0.03) carboxylate 6 - [N- (2,4-difluorophenyl) sulfamoyl] -3-t-butyl-1-cyclohexene-1-ethyl, each as white crystals. More polar diastereoisomer (compound 79): 1 H-NMR (d 6 -DMSO) d: 0.91 (9H, s), 1.10 (3H, t, J = 7.2Hz), 1.35-1 , 51 (1H, m), 1.90-2.30 (4H, m), 4.04 (2H, q, J = 7.2Hz), 4.40 (1H, d, J = 4.6Hz) , 7.02-7.14 (1H, m), 7.13 (1H, br), 7.41-7.53 (2H, m), 9.85 (1H, s). Calculated values (%) for C 19 H 25 F 2 NO 4 S: C, 56.84; H, 6.28; N, 3.49 Found (%): C, 56.77; H-6.04; N, 3.64 Less polar diastereoisomer (compound 80): 1 H-NMR (d 6 -DMSO) d: 0.93 (9H, s), 1.07 (3H, t, J = 7.0Hz), 1.58-2.43 (5H, m), 4.02 (2H, q, J = 7.0Hz), 4.24 (1H, d, J = 4.8Hz), 7.03-7.12 (1H, m), 7.11 (1H, br), 7.27-7.55 (2H, m), 9.86 (1H, s). Calculated values (%) for C 19 H 25 F 2 NO 4 S: C, 56.84; H, 6.28; N, 3.49 Found (%): C, 56.75; H, 6.15; N-3.66. Example 72 By a method similar to that indicated in Example 71, ethyl 5-t-butyl-2-chlorosulfonyl-1-cyclohexene-1-carboxylate (0.74 g), obtained by the method a indicated in the example reference 16, reacted with 2-chloro-4-fluoroaniline (0.45 g) to form a more polar diastereoisomer (compound 81; 0.04 g) and a less polar diastereoisomer (compound 82; 0.02 g ) ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3-t-butyl-1-cyclohexene-1-ethyl carboxylate, each in the form of white crystals. More polar diastereoisomer (Compound 81): 1H-NMR (d6-DMSO) d: 0.91 (9H, s), 1.08 (3H, t, J = 7.0Hz), 1.38-1, 53 (1H, m), 1.92-2.31 (4H, m), 4.04 (2H, q, J = 7.0Hz), 4.41 (1H, d, J = 6.6Hz), 7.14 (1H, br), 7.19-7.27 (1H, m), 7.48-7.57 (2H, m), 9.73 (1H, s). Calculated values (%) for C 19 H 25 ClFNO 4 S: C-54.60; H-6.03; N, 3.35 Found (%): C, 54.35; H, 5.89; N-3.51 Less polar diastereoisomer (compound 82): 1H-NMR (d6-DMSO) d: 0.92 (9H, s), 1.05 (3H, t, J = 7.0Hz), 1.59-2.55 (5H, m), 4.00 (2H, q, J = 7.0Hz), 4.26 (1H, d, J = 4.6Hz), 7.10 (1H, br ), 7.20-7.30 (IH, m), 7.49-7.58 (2H, m), 9.73 (IH, s). Calculated values (%) for C 19 H 25 CIFNO 4 S: C-54.60; H-6.03; N, 3.35 Found (%): C, 54.42; H, 5.99; N-3.38. Example 73 2,4-difluoroaniline (1.51 g) was dissolved in ethyl acetate (33 ml) and the resulting solution was mixed with triethylamine (2.51 ml), chilled with ice and then added dropwise. a solution of 2-chlorosulfonyl-5,5-dimethyl-1-cyclohexene-1-ethyl carboxylate (2.53 g), prepared by method a indicated in reference example 18, in ethyl acetate (17 ml). The reaction mixture was stirred under nitrogen flow at 0 ° C for 30 minutes, then at room temperature for 64.5 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with water (120 mL), 0.5 N HCl (120 mL), aq (120 mL x 2), and saturated brine (120 mL). The ethyl acetate layers were dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography over silica gel (eluent: ethyl acetate / hexane = 1/9 → 1/7). After feeding, the fractions were concentrated under reduced pressure and the residues were crystallized from a mixture of ethyl acetate and diisopropyl ether to give 6- [N- (2,4-difluorophenyl) sulfamoyl] -3,3-dimethyl-1-cyclohexene carboxylate. -1 ethyl (compound 83; 0.83 g) as white crystals. 1 H-NMR (d 6 -DMSO) d: 0.99 (3H, s), 1.08 (3H, t, J = 7.0Hz), 1.08 (3H, s), 1.39-1 , 45 (1H, m), 1.88-2.12 (2H, m), 2.30- 2.37 (1H, m), 4.01 (2H, q, J = 7.0Hz), 4 , 23 (1H, d, J = 4.4Hz), 6.79 (1H, s), 7.04-7.08 (1H, m), 7.12-7.36 (1H, m), 7 , 42-7.54 (1H, m), 9.88 (1H, s). Values calculated (%) for C 17 H 21 F 2 NO 4 S: C-54.68; H, 5.67; N, 3.75 Found (%): C, 54.59; H, 5.72; N-3.72. Example 74 By a method similar to that indicated in Example 73, ethyl 2-chlorosulfonyl-5,5-dimethyl-1-cyclohexene-1-carboxylate (0.62 g), obtained by the method a indicated in the reference example 18, reacted with 2-chloro-4-fluoroaniline (0.42 g) to give 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3,3-dimethyl-1-cyclohexene carboxylate. 1 ethyl (compound 84; 0.13 g) as white crystals. 1 H-NMR (d 6 -DMSO) d: 0.99 (3H, s), 1.05 (3H, t, J = 7.0Hz), 1.08 (3H, s), 1.40-1 , 45 (1H, m), 1.90-2.11 (2H, m), 2.36-2.43 (1H, m), 4.00 (2H, q, J = 7.0Hz), 4 , 24 (1H, d, J = 4.4Hz), 6.79 (1H, s), 7.20-7.30 (1H, m), 7.5-7.57 (2H, m), 9 . 77 (IH, s). Calculated values (%) for C 17 H 21 ClFNO 4 S: C, 52.37; H, 5.43; N, 3.59 Found (%): C, 52.30; H 5.28; N-3.62. Example 75 For a solution of ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (100 mg) prepared by method a indicated in example 3 in chlorobenzene (2 ml) , N-bromosuccinimide (56.7 mg) and 2,2'-azobisisobutyronitrile (0.5 mg) were added and the mixture was stirred at 90 ° C for 7 hours. The reaction mixture was combined with the ice-water mixture (20 ml), extracted with ethyl acetate (20 ml), washed with saturated brine (20 ml) and dried over anhydrous sodium sulfate. The solvent was distilled off and the obtained residue was purified by flash column chromatography on silica gel (eluent: ethyl acetate / hexane = 1/20 × ethyl acetate / hexane = 1/10) and crystallized from hexane to afford Ethyl 3-bromo-6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-ethyl carboxylate (compound 85, 27 mg) as colorless powdered crystals. 1 H-NMR (d 6 -DMSO) d: 1.04 (3H, t, J = 7.0 Hz), 2.03-2.20 (2H, m), 2.42-2.77 (2H, m), 4.05 (2H, q, J = 7.0Hz), 4.42 (1H, d, J = 5.4Hz), 5.32 (1H, t, J = 4.0Hz), 7, 07 (1H, d, J = 4.8Hz), 7.06-7.16 (1H, m), 7.31-7.55 (2H, m), 10.07 (1H, s). Calculated values (%) for C 15 H 16 BrF 2 NO 4 S: C, 42.46; H, 3.80; N-3.30 Found (%): C-42.4 Typical examples of a compound according to the invention are shown in Tables 1 to 5, but the compounds according to the invention are not limited thereto. T a b l i c a 1PL 203 663 B1 51 cont. table 1PL 203 663 B1 52 cont. table 1PL 203 663 B1 53 cont. table 1PL 203 663 B1 54 cont. table 1PL 203 663 B1 55 cd. table 1PL 203 663 B1 56 cont. table 1PL 203 663 B1 57 cont. Table 1 PL 203 663 B1 58 T a b 1 i c a 2 PL 203 663 B1 59 T a b 1 i c a 60 PL 203 663 B1 61 cont. Table 4PL 203 663 B1 62 T a b l i c a 5 Experience 1. Inhibitory Effect on NO Production The murine macrophage cell line RAW264.7 was used as iNOS-inducible cells and the test compound was tested for% inhibition of NO production. Test compound was dissolved in 10 mM in N, N-dimethylformamide and diluted with RPMI-1640 agent at a concentration of 0.1 mM. The concentration was then adjusted using this agent to obtain a final concentration ranging from 10 µM to 10 nM over a 10-fold dilution series, and the test compound was then added to the culture medium. The day before the experiment, cells were adjusted at 5 x 10 5 / ml in RPMI-1640 supplemented with 10% ice-inactivated calf serum and inoculated into a 96-well microplate at 1 x 10 5 cells. / 0.2 ml per well e. After incubating at 37 ° C in 5% CO 2/95% air overnight, test compound adjusted as described above was added and then LPS and gamma interferon were added at final concentrations of 5 ng / ml, respectively. and 1 U / ml. After further incubation overnight, the culture supernatants were tested for the concentration of nitrite ion (stable metabolite of NO), which was used as an indicator for NO production. The nitrite ion concentration was determined by adding 25 µl of 20 µg / ml 2,3-diaminonaphthalene (DAN) to 50 µl of culture supernatant followed by incubation at room temperature for 10 minutes, followed by the addition of 25 µl of 0.5N NaOH. and the fluidity was determined at a wavelength of 450 nm (excitation wavelength: 365 nm). The results are shown in Table 6. IC 50 is the concentration of a test compound that inhibits 50% of NO production. T a b l i c a 6 IC 50 Compound Number (µM) 1 2 1 0.12-0.32 2 1.1 3 0.013-0.039PL 203 663 B1 63 cont. table 6 1 2 4 2.6 5 3.7 6 0.59 7 4.0 8 4.8 9 4.1 10 0.058 11 0.31 12 0.18 13 0.46 14 0.59 15 0.28 16 0.18 17 2.6 18 4.4 19 2.0 20 0.005 21 2.4 22 0.18 23 0.027 24 0.78 25 0.32 26 3 27 0.25 28 0.029 29 0.0093 30 0 , 54 31 0.23 32 0.23 PL 203 663 B1 64 cd. table 6 1 2 33 0.26 34 0.35 35 0.082 36 1.5 37 0.13 38 0.041 39 0.32 40 2.5 41 0.24 42 1.1 43 0.073 44 3.7 45 0.027 46 0.054 47 0.048 48 3.8 49 5.6 50 2.0 51 4.0 52 4.3 53 2.4 54 2.3 55 3.3 56 1.0 57 4.6 58 0.39 59 0.54 60 7.9 61 2.8PL 203 663 B1 65 cd. Table 6 1 2 62 3.8 63 8.4 64 0.25 65 0.32 66 8.1 67 6.0 68 5.1 69 6.8 70 0.35 In Table 6, compounds 1 and 9 were tested 7 and 9 times respectively, and the minimum and maximum IC 50 are indicated. Any test compound showed a strong inhibitory effect on NO production by RAW264.7 cells, revealing that the oxazole derivative according to the invention had an excellent inhibitory effect on NO production. Experience 2. Inhibitory effect on cytokine production Using the murine macrophage cell line RAW264.7, the test compound was tested for its% inhibition of cytokine production. Test compound was dissolved at 10 mM in N, N-dimethylformamide and diluted with RPMI-1640 at 0.1 mM. The concentration was then adjusted using the agent to obtain a final concentration ranging from 10 µM to 10 nM over a 10-fold dilution series, and test compound was then added to the culture medium. On the day n before the experiment, cells were adjusted to 5 x 10 5 / ml in RPMI-1640 supplemented with 10% ice-inactivated serum and calves and inoculated into a 96-well microplate at 1 x 10 5 cells / 0.2 ml per well e. After incubating at 37 ° C in 5% CO 2/95% air overnight, test compound adjusted as described above was added and then LPS and gamma interferon were added at final concentrations of 5 ng / ml and 1 U, respectively. / ml. After further overnight incubation, culture supernatants were tested for TNF-a and IL-6 concentration. IL-1a was determined using 1.0 µg / ml LPS in the absence of gamma interferon and similar to other conditions. Each cytokine sentence was determined using a test kit manufactured by Amersham. The results are shown in Table 7. IC 50 is the concentration of test compound that inhibits 50% of cytokine production. T a b l i c a 7 IC 50 compound number (µM. ) TNF-? IL-1? IL-6 1 0.20 0.53 0.39 0.061 0.014 in Table 7, TNF-? And IL-6 were tested twice and each IC 50 is indicated. Experience 3. Effect on increasing nitric oxide levels in the blood When NO is produced in vivo as a result of defense mechanisms against infection or immune deficiency, it is readily metabolized to nitrous acid or nitric acid, resulting in an increase in the blood nitric oxide concentration ( NOx). Accordingly, experimental animals were used to investigate the effect of test compounds on the increase in blood NOx levels. Female BALB / c mice (6 weeks old) were purchased and acclimated for 1 week and assigned to groups with 6 to 8 animals each. In the treatment group, 30 mg / kg of a test compound suspended in a 0.5% aqueous solution of methylcellulose were orally administered. In the control group, the vehicle was given similarly. After 1 hour, LPS (10 mg / kg) was intraperitoneally administered to each animal in the treatment and control groups, and blood was drawn 6 hours after LPS administration and tested for plasma nitrite ion + nitrate ion. The nitrate ion was converted to a nitrite ion using nitrate reductase, and the measured values, which were obtained by the DAN-based fluoride method as described above, are reported as the total nitrate ion concentration. The% Inhibition in the treated group versus the control group is shown in Table 8. T a b l i c a 8 Compound number% NO inhibition in blood 1 76 3 90 Experience 4. Effect on the increase in the level of cytokines in the blood As a result of the defense mechanisms against infection or immune abnormalities, various cytokines are produced in vivo. Accordingly, an experimental animal model was used to investigate the effect of a test compound on increasing blood cytokine levels. Female BALB / c mice (6 weeks old) were purchased and acclimated for 1 week and assigned to groups of 6 to 8 animals each. In the treatment group, 30 mg / kg of test compound suspended in a 0.5% aqueous solution of methylcellulose was orally administered. In the control group, the vehicle was similarly administered. After 1 hour, LPS (10 mg / kg) was intraperitoneally administered to each animal in the treatment and control groups, and blood was drawn 6 hours after LPS administration and tested for plasma TNF-α levels. The concentrations of IL-1α, IL-1β and IL-6 were determined using plasma from blood drawn 6 hours after LPS administration. The% Inhibition in the treated group versus the control group is shown in Table 9. Each cytokine was determined using a test kit manufactured by Amersham. Table 9 Compound number% Inhibition of blood cytokines TNF-a IL-1 a IL-1 ß IL-6 1 98 97 73 89 As can be seen from tables 6 to 9, Compound (Ie) has an excellent inhibitory effect on NO production, inhibiting the effect on the production of cytokines, inhibiting the effect on increasing the concentration of nitric oxide in the blood and inhibiting the effect on increasing the concentration of cytokines. The compound numbers in Tables 6 to 9 correspond to the compound numbers in Tables 1 to 5. Industrial application The compound according to the invention (Iaa) and the compound (Ie) have an inhibitory effect on the production of nitric oxide (NO) and cytokines, and are useful as a prophylactic and therapeutic agent against diseases including heart diseases, autoimmune diseases, inflammatory diseases, diseases of the central nervous system, infectious diseases, sepsis, septic shock, etc. PL 203 663 B1 67 PL

Claims (51)

Claims 1. Cycloalkene derivatives of formula I: wherein R is OR 1 where R 1 is C 1-6 -alkyl, R 0 is hydrogen, ring n A is cycloalkene substituted with one or two selected substituents from a C 1-6 alkyl group, a halogen atom and a phenyl group, Ar is a C 6-14 aryl group, and optionally having two halogen atoms, is a group e of the formula: or of the formula and an is 2, or pharmaceutically acceptable salts. 2. Derivatives according to claim The process of claim 1, wherein ring nA is cycloalkene substituted with C 1-6 alkyl group, halogen atom or phenyl group and Ar is phenyl group optionally having two halogen atoms or a pharmaceutically acceptable salt thereof. 3. Cycloalkene derivatives of formula II: where R is OR 1 where R 1 is C 1-6 alkyl optionally substituted by a substituent selected from (1) hydroxyl, (2) carboxy, (3) ) a C 1-6 -alkoxycarbonyl group and (4) a C 6-10 -aryl group, R 0 is a hydrogen atom or a C 1-6 -alkyl group, or R and R 0 together are a bond, Ar is a group e C 6-14 aryl and optionally have a 1 to 3 substituents selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, nitro, cyano, halo C 1-4 alkyl, halo C 1-4 alkoxy, C 1-4 alkanoyl, 5-membered aromatic heterocyclic group selected from 1,2,3-tria- zolyl group, 1,2,4-triazolyl group and tetrazolyl group, C 1-4 alkoxycarbonyl-C 1-4 -alkyl carbamoyl group and 2,3-bis-t-butoxycarbonyl-guanidinomethyl group, eo pattern: or pattern ein is an integer from 1 to 3, provided that (i) R 1 is ethyl, R 0 is methyl and Ar is phenyl or (ii) R and R 0 together denote a bond and Ar is a phenyl group, e 2-methylphenyl group, e 4-bromophenyl group, e 4-methoxyphenyl group or e 2,6-dimethylphenyl group, then the group of the formula: denotes the eo group the formula: or a pharmaceutically acceptable salt thereof. 4. Cycloalkene derivatives according to claim 1 3, of formula III: wherein R 0 is hydrogen or C 1-6 alkyl, R 1 is C 1-6 alkyl optionally substituted with a substituent selected from (1) hydroxy, ( 2) a carboxyl group, (3) a C 1-6 alkoxycarbonyl group and (4) a C 6-10 aryl group, Ar is an e C 6-14 aryl group and optionally having 1 to 3 substituents selected from the atom halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, nitro, cyano, halo C 1-4 alkyl, halo C 1-4 - alkoxy, C 1-4 alkanoyl, 5-membered aromatic heterocyclic group selected from 1,2,3-triazolyl group, 1,2,4-triazolyl group and tetrazolyl group, C 1-4 alkoxycarbonyl group -C 1-4 -alkyl-carbamoyl and 2,3-di-t-butoxycarbonylguanidinomethyl, is a group a with the formula: or n) is an integer from 1 or 3 provided that Ar is the group e phenyl and R 1 is ethyl and R 0 is methyl, then a group of formula: is a group of formula: or a pharmaceutically acceptable salt thereof. 5. Derivatives according to claim 4. The compound of claim 4, wherein R1 is ethyl. 6. Derivatives according to claim 4, of formula III, wherein R 0 is hydrogen. 7. Derivatives according to claim 4, of formula III, wherein Ar is phenyl and optionally having substituents as defined in claim 4 4. 8. Derivatives according to claim 4, of formula III, wherein Ar is phenyl substituted with halogen and / or C 1-4 alkyl. 9. Derivatives according to claim 1 4, of the formula III, in which Ar is the group e of the formula: wherein R 4 and R 5 are the same or different and represent a halogen atom or a group e C 1-4 alkyl, and n 'is an integer and from 0 to 2. 10. Derivatives according to claim 9. The halogen atom is a fluorine atom or a chlorine atom. 11. Derivatives according to claim 1 In which the group of formula: is a group of formula: in which n has the same meaning as defined in claim 4, 4. 12. Derivatives according to claim 4, of formula III, wherein n is 1. 13. Derivatives according to claim 4, of formula III, wherein Ar is phenyl and optionally having substituents as defined in claim 4 4 and n is 1PL 203 663 B1 70 14. Cycloalkene derivatives according to claim 1, 3, of formula IV: in which Ar is a C 6-14 aryl group and optionally have a 1 to 3 substituents selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 -alkoxycarbonyl, nitro, cyano, halo-C 1-4 -alkyl, halo-C 1-4 -alkoxyl, C 1-4-alkanoyl, 5-membered group an aromatic heterocyclic group selected from 1,2,3-triazolyl, 1,2,4-triazolyl and tetrazolyl, C 1-4 alkoxycarbonyl-C 1-4 -alkylcarbamoyl and 2,3-di-t- butoxycarbonyloguanidinomethyl, and n is an integer from 1 to 3 or a pharmaceutically acceptable salt thereof. 15. Derivatives according to claim 15 14, of formula IV, wherein Ar is phenyl and optionally having substituents as defined in claim 14, 14 and n is 2. 16. Cycloalkene derivatives according to claim 1, 3, of formula V: wherein R 0 is hydrogen or C 1-6 alkyl, R 1 is C 1-6 alkyl optionally substituted by a substituent selected from (1) hydroxy, ( 2) a carboxyl group, (3) a C 1-6 alkoxycarbonyl group and (4) a C 6-10 aryl group, Ar is an e C 6-14 aryl group and optionally having 1 to 3 substituents selected from the atom halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, nitro, cyano, halogen-C 1-4 alkyl, halo C 1-4 - alkoxy, C 1-4 alkanoyl, 5-membered aromatic heterocyclic group selected from 1,2,3-triazolyl group, 1,2,4-triazolyl group and tetrazolyl group, C 1-4 alkoxycarbonyl group -C 1-4 -alkylcarbamoyl and 2,3-di-t-butoxycarbonyluanidinomethyl, wherein the group of formula: is the group e of the formula or provided that when Ar is phenyl, R1 is ethyl and R0 is methyl, it's a group of the formula: is group e of the formula or a pharmaceutically acceptable salt thereof, 17. Derivatives according to claim 16, of formula V, wherein R 1 is ethyl. 18. Derivatives according to claim 16, of formula V, wherein R 0 is hydrogen. 19. Derivatives according to claim 16, of formula V, wherein Ar is phenyl and optionally having substituents as defined in claim 16, 16. 20. Derivatives according to claim 16, of formula V, wherein A is phenyl substituted with halogen and / or C 1-4 alkyl. 21. Derivatives according to claim 16, o, formula V, in which Ar is the group e of the formula: wherein R 4 and R 5 are the same or different and represent a halogen atom or the group e C 1-4 alkyl, and n 'is the number ca total from 0 to 2. 22. Derivatives according to claim 21, wherein the halogen atom is a fluorine atom or a chlorine atom 23. Derivatives according to claim 16, wherein the group of formula: is a group of formula 24. Derivatives according to claim 16, of formula V, wherein R 0 is hydrogen and Ar is phenyl substituted with halogen. 25. A derivative according to claim 1 16, which is ethyl d-6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate, or a pharmaceutically acceptable salt thereof. 26. A cycloalkene derivative according to claim 1 16, which is ethyl 6- [N- (2,4-dichlorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate, or a pharmaceutically acceptable salt thereof. 27. A cycloalkene derivative according to claim 1 16, which is ethyl 6- [N- (2-chloro-4-methylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate, or a pharmaceutically acceptable salt thereof. 28. A cycloalkene derivative according to claim 1 16, which is ethyl d-6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate, or a pharmaceutically acceptable salt thereof. 29. A process for the preparation of cycloalkene derivatives as defined in claim 1 A compound according to claim 4, characterized in that the compound of formula: wherein R 1 and n have the same meanings as given in claim 4, 4 and X 1 is halogen, or a pharmaceutically acceptable salt thereof, is reacted with a compound of formula: wherein R 0 and Ar have the same meaning as in claim 1, 4, or with a pharmaceutically acceptable salt thereof. 30. A process for the preparation of cycloalkene derivatives as defined in claim 1 14, characterized in that the compound of formula: wherein n and Ar have the meaning given in claim 1, 14, or a pharmaceutically acceptable salt thereof, is subjected to a ring closure reaction in the presence of a condensing agent consisting of N, N-dicyclohexycarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, diethyl cyanophosphate, diphenylphosphorylazide or carbonyldiimidazole. 31. A process for the preparation of cycloalkene derivatives as defined in claim 1 16, characterized in that the compound of formula: wherein R 1 is as defined in claim 16; 16, and X 1 is halogen, or a pharmaceutically acceptable salt thereof, is reacted with a compound of formula: wherein R 0 and Ar are as defined in claim 1 16, or a pharmaceutically acceptable salt thereof. 32. A pharmaceutical composition containing the active ingredient and pharmaceutically acceptable excipients, characterized in that the active ingredient is the cycloalkene derivative of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof. 33. A pharmaceutical composition containing the active ingredient and pharmaceutically acceptable excipients, characterized in that the active ingredient is the cycloalkene derivative of formula II according to claim 3 or a pharmaceutically acceptable salt thereof. 34. The pharmaceutical composition of claim 34 33. A method according to claim 33, characterized in that the active ingredient is a cycloalkene derivative of formula III as defined in claim 4 or a pharmaceutically acceptable salt thereof. 35. The pharmaceutical composition according to claim 35 A compound according to claim 33, characterized in that the active ingredient is a cycloalkene derivative of formula IV as defined in claim 14, or a pharmaceutically acceptable salt thereof. 36. The pharmaceutical composition according to claim 36 A compound according to claim 33, characterized in that it comprises a cycloalkene derivative of formula V as defined in claim 16 or a pharmaceutically acceptable salt thereof as active ingredient. 37. The use of a cycloalkene derivative of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of a cardiac disease, autoimmune disease or septic shock. 38. The use of a cycloalkene derivative of formula II as defined in claim 3 or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or treatment of a cardiac disease, autoimmune disease or septic shock. 39. The use of a cycloalkene derivative of formula III as defined in claim 1 4 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of a cardiac disease, autoimmune disease or septic shock. 40. Use of a cycloalkene derivative of formula IV as defined in claim 1 14 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of a cardiac disease, autoimmune disease or septic shock. 41. The use of a cycloalkene derivative of formula V as defined in claim 1 16 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of a cardiac disease, autoimmune disease or septic shock. 42. The pharmaceutical composition of claim 42 32 for use as a medicament for the prevention or treatment of a disease requiring the inhibition of nitric oxide and / or cytokine production. 43. The pharmaceutical composition according to claim 1 The method of claim 42 for use in the prevention or treatment of a cardiac disease, autoimmune disease or septic shock. 44. The pharmaceutical composition of claim 44. 33 for use as a medicament for the prevention or treatment of a disease requiring the inhibition of nitric oxide and / or cytokine production. 45. The pharmaceutical composition according to claim 45 44, characterized in that it is used for the prevention or treatment of cardiac disease, autoimmune disease, or septic shock. 46. A pharmaceutical composition as defined in claim 1 34 for use as a medicament for the prevention or treatment of a disease requiring the inhibition of nitric oxide and / or cytokine production. 47. The pharmaceutical composition according to claim 47 46 for use in the prevention or treatment of a cardiac disease, autoimmune disease or septic shock. 48. The pharmaceutical composition of claim 48 For use as a medicament for the prevention or treatment of a disease requiring the inhibition of nitric oxide and / or cytokine production. 49. The pharmaceutical composition according to claim 49 48, characterized in that it is used for the prevention or treatment of cardiac disease, autoimmune disease or septic shock. 50. A pharmaceutical composition as defined in claim 50 36 for use as a medicament for the prevention or treatment of a disease requiring the inhibition of nitric oxide and / or cytokine production. 51. A pharmaceutical composition according to claim 1, 50, characterized by the fact that it is used as an agent for the prevention or treatment of cardiac disease, autoimmune disease or septic shock. PL 203 663 B1 74 Department of Publications of the Polish Patent Office Price 6.00 PLN per l.